The p.Gly2019Ser is the commonest pathogenic mutation in the LRRK2 gene among Egyptians with familial and sporadic Parkinson's disease

The p.Gly2019Ser is the commonest pathogenic mutation in the LRRK2 gene among Egyptians with familial and sporadic Parkinson's disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The p.Gly2019Ser is the commonest pathogenic mutation in the LRRK2 gene among Egyptians with familial and sporadic Parkinson's disease Mohamed Salama, Martina William, Sharifa Hamed, Ali Shalash, Eman Khedr, and 28 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4456878/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Nov, 2024 Read the published version in npj Parkinson's Disease → Version 1 posted 11 You are reading this latest preprint version Abstract The impact of LRRK2 variants on the risk of Parkinson's disease (PD) in Egyptians remains unknown. We examined 1,210 Egyptians (611 PD patients and 599 controls) for 12 LRRK2 mutations. The p.Gly2019Ser was the only variant detected across Egypt, with a prevalence of 4.1% in sporadic cases, 6.5% in familial cases, and 0.68% in controls. Among p.Gly2019Ser carriers, all were heterozygous bar one homozygous patient, and all shared the common haplotype 1. Demographics and UPDRS scores did not differ between carriers and non-carriers, with most patients being males and developed PD in their fifties. Early-onset PD prevalence was 33% in carriers and 25% in non-carriers. Familial cases were 16% in carriers and 11% in non-carriers. This study affirms that like other North Africans and Mediterranean populations, Egyptians with PD have a notably high prevalence of the p.Gly2019Ser. LRRK2 inhibitors could be promising therapeutic options for further exploration in this population. LRRK2 Egyptians Parkinson’s Disease Genetics Mutation p. Gly2019Ser Figures Figure 1 Figure 2 Introduction Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms such as tremors, stiffness, and bradykinesia, in addition to other non-motor symptoms including anxiety, depression, constipation, and orthostatic hypotension. While aging is the primary risk factor for PD, research suggests a significant influence of genetic and environmental factors in the development of the disease 1,2 . In the past two decades, advances in genetics have greatly enhanced our understanding of the molecular mechanisms leading to the development of PD 3,4 . One promising area of PD research is the role of the LRRK2 protein and its enzymatic activity. PD related pathogenic mutations in LRRK2 gene can increase this activity, making it an attractive target for novel neuroprotective drugs with kinase inhibitors potentials 5–7 . To date, there have been extensive studies on various PD related LRRK2 variants, with at least 20 classifieds as "pathogenic," and others considered likely pathogenic or of uncertain significance 5,8 . It is widely recognized that LRRK2 variants linked to PD exhibit diverse geographic and ancestral distributions 8,9 . For instance, the well-known p.Gly2019Ser mutation has a higher prevalence in PD patients from North African and Ashkenazi Jewish backgrounds compared to individuals of European ancestry 10 . The p.Arg1441Gly mutation, on the other hand, is notably common in the Basque population, contributing to almost half of familial PD cases in that region 11 . Variants like p.Gly2385Arg and p.Arg1628Pro are more frequently observed in PD patients of East Asian descent 9,12 . The pathogenic variant p.Asn1437Ser is mainly found in Germans, while p.Asn1437His is more prevalent in Scandinavians, and p.Asn1437Asp is common in the Chinese population 13 . Other few rare LRRK2 mutations were exclusively found in specific families such as the p.Tyr1699Cys variant was observed in a German Canadian family 14 , and the p.Ile2020Thr mutation was detected in a Japanese family with a single-founder effect 15 . Notably, to date no disease-causing LRRK2 PD mutation was reported in individuals of sub-Saharan African descent. Knowledge about the prevalence of the pathogenic LRRK2 variants in Egyptians is lacking. To date only three studies are available with a limited number of patients included. Hashad and colleagues 16 examined the prevalence of LRRK2 p.Gly2019Ser mutation in a cohort of 113 Egyptian patients with sporadic PD and 87 healthy controls from lower Egypt, specifically Alexandria and nearby regions. Of the PD patients, 11 individuals (9.7%) tested positive for the p.Gly2019Ser mutation, all of whom were heterozygous. None of the individuals in the control group had the mutation. El Desoky et al 17 assessed the LRRK2 p.Gly2019Ser in 69 individuals with sporadic PD and 96 matched controls from Assiut Governorate and nearby regions in upper Egypt. Out of the 69 PD patients, only one individual (1.45%) was found to be a heterozygous carrier of the p.Gly2019Ser mutation. None of the other participants, both patients and controls, had the mutation. The authors hypothesized that the prevalence of p.Gly2019Ser is lower among Egyptians residing in Upper Egypt compared to those living in North Egypt. However, they concluded that a multicenter study should be conducted on a larger cohort of Egyptians with PD to accurately determine the prevalence of the p.Gly2019Ser mutation. Lastly, Shan & Wszolek 18 reported on the first case of familial PD in an Egyptian family caused by the LRRK2 Arg1441Cys mutation. The proband is a male patient, aged 57, with two affected parents. He experienced his first symptoms when he was 49 years old and presented with a unilateral typical akinetic-rigid syndrome which responded well to carbidopa/levodopa therapy. Situated at the crossroads of Africa, the Middle East, and Europe, Egypt possesses distinctive characteristics in terms of geography, geopolitics, and history. Egypt's unique location has played a role in shaping the genetic composition of its people through historical invasion and migratory events. The modern-day Egyptians represent a homogeneous population with exclusive genetic variants and unique genetic admixture from Europeans, Arabs, Asians, and Africans ancestries 19 . Egypt, with a population of over 110 million, is the fourteenth most populous country in the world and the third most populous country in Africa 20 . As the number of elderly individuals in Egypt increases and life expectancy rises, it is expected that there will be a significant increase in the number of people developing neurodegenerative disorders such as PD 21 . Although exact statistics are not readily available, the limited information suggests that the prevalence of PD in Egypt could be around 500 cases per 100,000 individuals, which is among the highest rates globally 22,23 . To ensure that this expanding and ancestrally distinct patient population can take advantage of the progress being made in the diagnosis and treatment of PD, it is crucial to comprehensively examine their genetic makeup and risk to the disease. The International Parkinson’s Disease Genomic Consortium Africa (IPDGC Africa), a consortium dedicated to advancing the understanding of PD in Africans 24 , has previously investigated the PD genetic risks associated with LRRK2 in a large cohort of Nigerians from sub-Saharan Africa 25,26 . The current report showcases the progress of this consortium and presents the findings from the second cohort of its members in Egypt and represents the most extensive and thorough investigation of LRRK2 PD related variants conducted in Egyptians to date. Results Recruitment and cohort’s characteristics A total of 1,210 participants were included in this study: 611 patients with PD (64.8% male) and 599 unrelated healthy controls (43.4% male). The recruitment process took place in 16 governorates, covering 90% of the inhabited regions, across Egypt: 12 in lower Egypt and 4 in upper Egypt. All participants self-identified as native Egyptians for at least two generations. Figure 1 illustrates the distribution of recruitment sites throughout Egypt and the number of participants (cases and controls) recruited at each site. Notably, approximately 70% of the cohort participants (PD 422, Controls 422) were recruited from lower Egypt, while 30% of the participants (PD 189, Controls 177) were from upper Egypt. The mean ± SD age of PD patients at recruitment was 61.01 ± 9.67 years (range: 31–94), while the mean ± SD age at recruitment of controls was 43 ± 14 years (range: 17–90). Among PD patients, 4.91% (30/611) had their first symptoms before 40, and 24.55% (150/611) developed PD before turning 50. Family history of PD was identified in 11.46% (70/611) of patients. Consanguinity was uncommon, present in only 3.6% of the patients' families. The mean age at diagnosis was 54.33 ± 8.68 years (range 21–83), which aligns with the mean age at onset of initial motor symptoms at 53.81 ± 8.56 years (range 21–83). The mean ± SD MDS Unified Parkinson's Disease Rating Scale (UPDRS) score for patients was 100.35 ± 49.96 (range: 7-231). Supplementary table 1 lists the demographic and UPDRS scores of the study participants and compare these characteristics between individuals from lower and upper Egypt. Except for the age of the patients during the study, duration of illness and the MDS UPDRS scores at the time of study, there were no significant differences observed between PD patients from upper and lower Egypt. At the time of the study, patients from Upper Egypt were, on average, approximately 2 years younger than those from Lower Egypt. Additionally, the duration of their illness was, on average, 3 years shorter, and their UPDRS scores were about 10 points higher compared to patients from Lower Egypt (P value < 0.001). Notably, there were no significant differences in the age of onset between the two groups (Upper Egypt 53.66 ± 8.13 years (range 27–83), Lower Egypt 53.88 ± 8.71 years (21–79): U 38971.50, p value 0.652) LRRK2 pathogenic SNPs in patients and controls A validated allele Specific fluorescence-based PCR assays (KASP assays) were used to genotype 12 pathogenic LRRK2 SNPs. The assay performed effectively and clearly distinguished genotyping clusters for all 12 SNPs. The allelic frequencies for all SNPs were in Hardy-Weinberg equilibrium (p = 0.88-1). In both the PD patients and controls, only the p.Gly2019Ser mutation was detected, while the other 11 LRRK2 pathogenic variants were not found. A summary of the genotyping results for the 12 LRRK2 SNPs is provided in Supplementary Table 2. Among the participants who were successfully genotyped for p.Gly2019Ser, 4.38% (24/547) of PD patients and 0.68% (4/587) of healthy controls were found to carry the pathogenic p.Gly2019Ser allele. As expected, the p.Gly2019Ser is significantly associated with PD status (OR 6.688, 95% CI 2.305–19.403, p-value 0.0001). The p.Gly2019Ser Minor Allelic Frequencies distribution in patients (MAF ~ 0.023) and in controls (MAF ~ 0.003) were uniform across Egypt with no significant differences observed between upper and lower regions ( X 2 0.1367, p-value: 0.71). The carrier rate was 6.45% (4/62) in familial PD cases and 4.12% (20/485) in non-familial cases. Table 1 details the Genotypic and Allelic frequencies of the p.Gly2019Ser in this cohort, including a breakdown of its distribution in upper and lower Egypt. Table 1 Genotypic and allelic frequencies of the LRRK2 p.Gly2019Ser in carriers vs noncarriers Region Genotype frequencies Allele frequencies GG GA AA G A Across Egypt All Cases (547) Familial (62) Sporadic (485) 523 (0.956) 58 (0.935) 465 (0.959) 23 (0.042) 3 (0.048) 20 (0.041) 1 (0.002) 1 (0.016) 0 (0.000) 1069 (0.977) 119 (0.960) 950 (0.979) 25 (0.023) 5 (0.040) 20 (0.021) Controls (587) 583 (0.993) 4 (0.007) 0 (0.000) 1170 (0.997) 4 (0.003) Upper Egypt Cases (186) 177 (0.952) 9 (0.048) 0 (0.000) 363 (0.976) 9 (0.024) Controls (177) 176 (0.994) 1 (0.006) 0 (0.000) 353 (0.997) 1 (0.003) Lower Egypt Cases (361) 346 (0.958) 14 (0.039) 1 (0.003) 706 (0.978) 16 (0.022) Controls (410) 407 (0.993) 3 (0.007) 0 (0.000) 817 (0.996) 3 (0.004) Demographic, clinical characteristics and haplotype of the p.Gly2019Ser carriers Among the 24 PD patients with the p.Gly2019Ser mutation, 15 were recruited from Lower Egypt and 9 were from Upper Egypt, with a male predominance of 70.83%. The average age at recruitment of these patients was 59.67 ± 8.32 years (range:42–79), while the mean age of disease onset was 52 ± 8.07 years (range: 38–67). Most patients (79.17%) developed their first motor symptoms before the age of 60, with 4.17% experiencing symptoms before 40, 20.83% between 40 and 49, 45.83% between 50 and 59, and 20.83% between 60 and 69 years. Only 16% had a family history of PD, while 84% were sporadic cases. Consanguinity within the family was reported only in 4.17% (1/24). The Mean ± SD of MDS-UPDRS score for p.Gly2019Ser carriers with PD was 120.48 ± 59.61. There were no significant differences in demographic characteristics or UPDRS scores between p.Gly2019Ser PD carriers and non-carriers (see Table 2 ). Table 2 Demographic and clinical characteristics of p.Gly2019Ser carriers vs non-carriers Parameter Non-G2019S carriers (n = 523) G2019S carriers (n = 24) P-value * Gender distribution, n (%) Female Male 183 (34.99) 340 (65.01) 7 (29.17) 17 (70.83) 0.664 Age at Study (y),mean ± SD (range) 60.69 ± 9.79 (31–94) 59.67 ± 8.32 (42–79) 0.523 Age at onset (y), mean ± SD (range) 53.82 ± 8.67 (21–83) 52 ± 8.07 (38–67) 0.377 Young onset PD ( 0.9999 Early onset PD (< 50 y), n (%) 129 (24.67) 8 (33.33) 0.340 Age at Diagnosis (y), mean ± SD (range) 54.28 ± 8.77 (21–83) 52 ± 8.07 (38–67) 0.246 Family History n (%) 58 (11.09) 4 (16.67) 0.336 Duration of illness, mean ± SD (range) 6.88 ± 5.47 (0–33) 7.67 ± 5.90 (0–25) 0.393 MDS UPDRS mean ± SD (range) 118.83 ± 48.94 (7-223) 120.48 ± 59.61 (38–231) 0.151 * P values for categorical variables were calculated using Fisher's exact test and for continuous variables using the Mann-Whitney U test. The Four non-manifesting p.Gly2019Ser carriers in the control group were two females aged 26 and 29, and one male aged 55 from lower Egypt and one female aged 39, from upper Egypt. None of the control carriers reported a family history of PD. Table 3 details the characteristics and UPDRS scores of each of the 28 individuals (24 patients and 4 controls) who are positive for the p.Gly2019Ser pathogenic variant. This patient, a male from Upper Egypt, had a family history of PD on both parents. He first exhibited motor symptoms at 45 and initially responded well to levodopa therapy. However, his progressively worsened, and by the age of 54, when he joined the study, he began experiencing dyskinesia and rapid wearing-off effects. Table 3 Individual demographics and UPDRS scores of p.Gly2019Ser carriers No Phenotype Region % from total Governorate Gender Age (y) Age at onset (y) Family History Consanguinity UPDRS score 1 PD Lower Egypt 4.15% (15/361) Cairo Male 54 45 Yes No 139 2 PD Cairo Male 69 67 No No 230 3 PD Giza Male 53 45 No No 163 4 PD Giza Male 63 52 No No 72 5 PD Giza Female 54 40 No Yes 231 6 PD Qalyubia Male 55 53 No No 73 7 PD Cairo Male 58 58 No No 43 8 PD Cairo Male 55 55 No No 72 9 PD Mansoura Male 79 54 No No 223 10 PD Mansoura Female 60 40 No No 194 11 PD Banha Male 66 57 No No 100 12 PD Cairo Female 46 40 No No 69 13 PD Alexandria Female 42 38 No No Unavailable 14 PD Alexandria Male 49 42 No No 38 15 PD Alexandria Male 67 57 No No 87 16 PD Upper Egypt 4.84% (9/186) Asyut Male 63 61 No No 53 17 PD Asyut Male 59 49 Yes No 85 18 PD Asyut Female 54 52 Yes No 72 19 PD Asyut Male 59 50 Yes No 127 20 PD Asyut Male 65 60 No No 171 21 PD Asyut Male 68 62 No No 128 22 PD Asyut Female 62 56 No No 153 23 PD Asyut Male 62 55 No No 119 24 PD Asyut Female 70 60 No No 129 Summary Males (70.83%) Females (29.17%) 59.67 ± 8.32 (42–79) 52.00 ± 8.07 (38–67) Yes (16.67%) No (83.33%) 1/24 (4.2%) 120.48 ± 59.61 (38–231) 1 Control Lower Egypt Cairo Female 29 NA No No NA 2 Control Giza Male 55 NA No No NA 3 Control Cairo Female 26 NA No No NA 4 Control Upper Egypt Asyut Female 39 NA No No NA All p.Gly2019Ser carriers (except for one control sample that failed during genotyping) had at least one copy of the minor allele (A) of the rs28903073 SNP, suggesting they shared haplotype 1. This haplotype is widely recognized as the predominant haplotype for the p.Gly2019Ser mutation, commonly encountered in individuals carrying the p.Gly2019Ser pathogenic allele across Europe, North and South America, as well as North Africa 45 . Supplementary Fig. 1 illustrates the Sanger sequencing chromatograms of the rs28903073 SNP in individuals carrying the p.Gly2019Ser variant. Discussion It has been more than twenty years since the identification of LRRK2 as a genetic factor associated with both familial and sporadic PD 27,28 . Situated on chromosome 12, LRRK2 is among the most researched genes in PD. It consists of 51 exons spanning 144 kb and encodes a large 286 kDa multidomain protein of the same name. Over 300 genetic variants have been identified in LRRK2 , with at least 20 variants confirmed as pathogenic. These variations follow an autosomal dominant inheritance pattern and are primarily located in LRRK2’s catalytic core, which includes the ROC, COR, and Kinase domains. They result in enhanced LRRK2 autophosphorylation activity and increased phosphorylation of surrogate substrates, leading to a harmful kinase gain of function 5,13,29 . Inhibitors that control the activity of the LRRK2 kinase are among the most promising new drug targets for PD currently undergoing clinical trials 5 . The existing understanding of the genetic risk of PD in the Middle East and North Africa (MENA), particularly in Egypt, the most populous country in this region, is limited and relies mainly on preliminary data from case reports and small cohorts 16–18,30 . In this study our consortium reports on the largest multicenter investigation in Egyptians with PD to date. The study examined the prevalence of 12 LRRK2 variants with confirmed pathogenicity including the p.Gly2019Ser, among 611 PD patients and 599 controls from 16 out of Egypt's 27 governorates, encompassing around 90% of the nation's populated regions. The p.Gly2019Ser mutation was the only LRRK2 variant found in this cohort. None of the other 11 variants were detected. Carriers of the p.Gly2019Ser pathogenic allele were found across upper and lower Egypt, with a combined average prevalence of 4.4% (MAF 2.3%) among PD patients. This prevalence was higher in familial cases (6.4%) compared to sporadic patients (4.1%) and did not show significant variability between upper and lower regions. These results affirm the p.Gly2019Ser mutation as the most prevalent LRRK2 risk variant in Egyptians with PD, known to date. In addition, they suggest a widespread distribution of this mutation across the entire country, including Upper Egypt, contrary to previous reports that had localized its presence to Lower Egypt 16,17 . While the 4.4% prevalence rate of the p.Gly2019Ser variant in our cohort is below the 9.7% reported previously by Hashad et al. 16 , this figure still ranks among the highest ranges reported worldwide. It is noteworthy that the study conducted by Hashed et al has a significantly smaller sample size compared to our cohort and was limited to a single governorate in lower Egypt. Most PD patients carrying the p.Gly2019Ser mutation in our study developed symptoms in their forties and fifties. There were no significant variations in the age of onset, male predominance, or total UPDRS scores between those with and without the p.Gly2019Ser mutation. It is worth noting that the p. Gly2019Ser mutation was also identified among the control group at an average prevalence of 0.68% (MAF 0.3%). This figure again ranks among the highest reported rates in controls globally and is like those found in non-manifesting carriers within the Maghrib (0.7-2%) and Ashkenazi Jewish (0.4-2%) populations. Although two non-manifesting carriers are under 30 and might develop PD later in life, the presence of the p.Gly2019Ser mutation in two unaffected controls aged 39 and 55 indicates a reduced or incomplete penetrance of this variant in Egypt. Penetrance, which refers to the likelihood of an individual with the mutation developing PD by a specific age, exhibits a wide range of estimates for the p. Gly2019Ser mutation, ranging from 7–100% 31–33 . Factors such as ethnicity, gender, and the interplay of genetic and environmental factors can influence these penetrance rates 34 . Additional research, including longitudinal and familial studies, are necessary to determine the penetrance rates of the p.Gly2019Ser mutation in Egyptians and to identify factors that might modify this penetrance. An important observation in this study is that around one quarter of PD patients who did not have the p.Gly2019Ser mutation experienced symptoms before turning 50 years old. This percentage exceeds the global Early Onset Parkinson’s Disease (EOPD) rates of 3–14% and aligns closely with data from previous clinical and epidemiological studies on EOPD in Egypt 23,35,36 . Interestingly, the incidence of a family history of PD was relatively low, around 16% in p.Gly2019Ser carriers and 11% in non-carriers. consistent as well with previously reported rates in Egyptians (11–15%) 37,38 . Furthermore, the consanguinity rates among families of PD patients were below 5% in all regions. The coexistence of high EOPD rates and lack of family history of PD and (or) consanguinity in Egyptian patients present an intriguing scenario. EOPD is typically associated with higher genetic risks and tends to be hereditary 3,39 . Combining these observations with the fact that only 5% of EOPD cases in the cohort could be attributed to the LRRK2 p.Gly2019Ser mutation suggests that other genetic variants may be involved in the development of Parkinson's Disease (PD) among Egyptians 40 . We speculate that these variants are likely to be either recessive or arise as de novo mutations. Nonetheless, the absence of substantial familial rates hints at potential contributions of environmental factors as well 40 . Since the discovery of the p. Gly2019Ser mutation, numerous studies have investigated its date and origin in different populations, linking it to three distinct haplotypes identified as haplotype 1, 2, and 3 41 . Haplotype 1 is particularly prevalent among carriers of the mutation worldwide, identified in Europeans, Ashkenazi Jews, North Africans, and Latin Americans 42 . Haplotype 2 is present in individuals of European descent, while Haplotype 3 was first observed in Turkish and Japanese families. Haplotypes 2 and 3 are both extremely rare, less studied and seem to have emerged more recently compared to Haplotype 1 41 . Within our cohort, all individuals with the p.Gly2019Ser mutation shared Haplotype 1, suggesting a common ancestral founder with most carriers of the mutation in other populations. In the field of population genetics, it is commonly believed that the central point of origin for a mutation corresponds with where the mutation is most prevalent 43 . It is hypothesized that the founding event of the p.Gly2019Ser mutation likely occurred in the Near East about 4000–5000 years ago before spreading to Europe and other regions due to migratory movements 41,44,45 . Egypt is located at a critical juncture for historical migratory paths through which the p.Gly2019Ser could have been introduced to its population To the west, Egypt shares borders with Maghreb countries where the mutation is prevalent, particularly among Arab barbers, with rates of 39% in sporadic PD and 36% in familial PD cases 8 . In the east, the prevalence of the mutation is approximately 10.6% in sporadic PD cases and 26% in familial cases among Ashkenazi Jews, making them the second most affected ethnic group. Southern Mediterranean European countries exhibit higher frequencies of the mutation (2 − 4% in sporadic PD and 3 − 14% in familial PD) compared to Northern European nations (< 1 − 2% in sporadic PD and 0 − 3% in familial PD) 8 . Notably, the p.Gly2019Ser mutation is rare in Asian countries and absent in Sub-Saharan Africa 25,26 . It is plausible that the p.Gly2019Ser entered Egypt via the east-west axis during the migratory movements of Arab and (or) North African Berbers (referred to as the Maghrebi Effect) or through north-south axis by the maritime migrations across the Mediterranean, known as the "back to Africa" gene flow (Fig. 2 ). 46,47 . To fully identify the origin and transmission path of this mutation into Egypt and its environs, it is crucial to explore the genetic ancestries and migratory events within this population and adjacent nations. In conclusion, this study provides insight from the most extensive genetic investigation carried out on PD susceptibility in Egyptians to date. It verifies the high prevalence rates of the p.Gly2019Ser mutation in Egypt which are similar to the rates seen in Southern Mediterranean areas. Significantly, it confirms the presence of the p.Gly2019Ser mutation in individuals indigenous to upper Egypt. These findings place Egyptians at the forefront of populations that may be able to host and benefit from LRRK2 therapeutic programs that are presently in progress. However, our study raises several unresolved questions particularly regarding the penetrance rates and the route of entry of the p.Gly2019Ser mutation into Egypt. Moreover, the lack of clinical scales within this cohort has impeded the comprehension of clinical characteristics of patients including the understanding of both motor and non-motor symptoms, disease progression, and the efficacy of antiparkinsonian medications. Efforts are underway within our team to gather additional data to address these limitations. It is important to highlight as well that this study focused on assessing only 12 LRRK2 variants using a targeted approach. A more comprehensive analysis utilizing untargeted next generation whole exomes and whole genome sequencing methods are necessary in this population to investigate both known and novel PD variants, especially in cases of EOPD. Finally, we hope that our study will encourage further investigations on LRRK2 in the adjacent territories including the Levant, the Arabian Peninsula, and the Nile basin. It will be of interest to explore if the p.Gly2019Ser mutation presence extends beyond lower Egypt into countries that have had historical migratory links with Egypt, such as Sudan, Ethiopia, Oman, and Yemen. The exploration of the mutation's distributions in these regions poses an interesting question that warrants deeper exploration. Methods Participants recruitment The study was granted ethical approval by the Egyptian participating institutions review boards (Ethics Approval # 2021-2022-058 and 2021-2022-203), as well as University College London (UCL) ethical committee (REC # 22/NE/0080). Written informed consent was obtained from all participants at each study site in accordance with the Declaration of Helsinki and the Common Rule. One thousand two hundred and ten Egyptians, including 611 PD patients and 599 unrelated healthy controls, were recruited by the IPDGC Africa members through two established networks in Egypt. Specifically, 479 PD patients and 481 unrelated controls were recruited through the Egyptian Network of Neurodegenerative Diseases (ENND), which is a pan Egypt network formed in December 2013 and is based in multiple universities including Mansoura, Cairo, Ain-Shams, Al-Azhar, Alexandria, Assiut, Tanta, Zagazig, Menoufia, Sohag, Al-Minya, Banha, Suez Canal Universities, and The American University in Cairo. An additional 132 PD patients and 118 controls were included from an independent cohort from the University of Assiut. The recruitment process took place between 2011 and 2022. Only subjects who self-declared themselves and their both parents as native Egyptians were included in the study. PD patients were diagnosed by movement disorders specialists using the UK Brain Bank Criteria 48 and (or) the criteria established by the Movement Disorder Society Task Force 49 . Controls were unrelated-healthy individuals who do not have a history of PD or any other neurological condition. Basic demographic information including age, gender, self-declared ethnicity, age at disease onset (defined as age at experiencing first motor symptoms), and age at diagnosis (for cases only), were collected from all participants. The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) were also collected from patients. LRRK2 SNPs Genotyping DNA was extracted from either 10 mL of venous whole blood samples or saliva samples using established protocols. Genotyping was carried out using the Kompetitive Allele Specific Polymerase Chain Reaction assay (KASP; LGC Genomics, Herts, UK) as described previously 25 . Twelve LRRK2 single-nucleotide polymorphisms (SNPs) were selected for genotyping. These SNPs include rs34637584 (p.Gly2019Ser), rs34995376 (p.Arg1441His), rs74163686 (p.Asn1437His), rs35870237 (p.Ile2020Thr), rs35801418 (p.Tyr1699Cys), rs34410987 (p.Pro755-Leu), rs34778348 (p.Gly2385Arg), rs281865052 (p.Met1869Val), rs34594498 (p.Ala419Val), rs33949390 (p.Arg1628Pro), rs35808389 (p.Leu1114Leu), and rs34805604 (p.Ile1122Val). These SNPs were carefully chosen based on strict criteria, including replicated association studies, robust disease segregation data, functional evidence, and the availability of a validated KASP assay for each SNP. To ensure the pathogenicity of each SNP, we checked the ClinVar and MDS Gene databases 50,51 . Initially, we also included the SNP rs33939927, which codes for p.Arg1441Gly/Cys/Ser. However, we later determined that it was unsuitable for KASP genotyping due to its proximity to rs34995376 (p.Arg1441His) and its tri-allelic nature. The haplotype background for p.Gly2019Ser carriers was determined by genotyping the rs28903073. The “A” allele for this SNP has a frequency of < 0.1% and if observed indicates the presence of haplotype 1 45 . Variant specific primer was designed using primer 3 software ( http://bioinfo.ut.ee/primer3-0.4.0 ). PCR was performed using Touchdown with the following cycling conditions: 94°C for 10 minutes; 8 cycles of [30 seconds at 94°C, 30 seconds at 65°C, 45 seconds at 72°C]; 18 cycles of [30 seconds at 94°C, 30 seconds at (65 − 55°C), 45 seconds at 72°C]; 14 cycles of [30 seconds at 94°C, 30 seconds at 55°C, 45 seconds at 72°C; and a final extension step of 10 minutes at 72°C. SNP genotyping was performed using standard bi-directional Sanger sequencing. Data summaries and statistical analysis The cohort's demographics and clinical characteristics were summarized using appropriate descriptors including mean and standard deviation (SD) for continuous variables and percent frequency for categorical variables and compared between groups (PD and controls) using two-tailed χ2 test for categorical variables or non-parametric alternative for continuous variables as relevant. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) Statistics for Windows, version 29.0 (IBM Corp, Armonk, NY, USA). The genotyping data for SNPs were analyzed using SNP Viewer software (version 1.99; Hoddesdon, UK) and tested for Hardy-Weinberg equilibrium using the χ2 test. Results of the sanger sequencing were analyzed using SEQUENCHER (Version 5.4.5, Gene Codes Corporation, Inc). Data access Anonymized genotyping and clinical data can be provided to bone fide researchers upon request from the corresponding author(s). Declarations Author’s contributions: Conceptualization and design: Mie Rizig and Mohamed Salama Data acquisition: All authors. Drafting of manuscript: Martina B. William and Mie Rizig. Critical revision of manuscript for intellectual content: All authors. Statistical analysis: Martina B. William, Mohamed H. Yousef, and Mie Rizig. Administrative, technical, or material support: Mie Rizig and Mohamed Salama Supervision of genotyping: Mie Rizig and Mohamed Salama Data management: Mie Rizig and Mohamed Salama Funding acquisition: Mie Rizig, Henry Houlden, and Mohamed Salama Acknowledgments: We would like to thank the patients, their care partners, and the controls for their participation. Financial Disclosure: Mie Rizig received funding from the University College London Grand Challenges Small Grants (Award ID:177813), the MRC neurosciences and mental health research grant. April 2023 – April 2026 and The Michael J Fox Foundation Genetic Diversity in Parkinson’s Disease 2019 (Grant ID:17483). Henry Houlden received funding from the Michael J Fox Foundation Genetic Diversity in Parkinson’s Disease (Grant ID: 17483). Mohamed Salama received funding from the Bartlett Fund for Critical Challenges- 2021 (Agreement Number: 2 – Cycle 3) and the American University in Cairo Faculty Support Grant-2021 awarded to. The funders were not involved in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Conflict of Interest: All authors declare no conflict of interest. References Sakowski, S. A., Koubek, E. J., Chen, K. S., Goutman, S. A. & Feldman, E. L. Role of the Exposome in Neurodegenerative Disease: Recent Insights and Future Directions. Ann. Neurol. 95 , 635–652 (2024). Funayama, M., Nishioka, K., Li, Y. & Hattori, N. Molecular genetics of Parkinson’s disease: Contributions and global trends. J. Hum. 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18:57:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":337209,"visible":true,"origin":"","legend":"\u003cp\u003eRecruitment sites across all 16 governorates and the numbers of PD patients (N\u003csub\u003ePD\u003c/sub\u003e) and healthy controls (N\u003csub\u003eCT\u003c/sub\u003e) recruited from each site. Upper Egypt is delineated by a bold black border, while Lower Egypt is delineated by a bold blue border.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4456878/v1/4aad228a68d2aa4f8398186a.png"},{"id":59434804,"identity":"80f0c00b-852d-4c20-8e0d-7e288c5729c9","added_by":"auto","created_at":"2024-07-01 19:05:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1063792,"visible":true,"origin":"","legend":"\u003cp\u003eA map illustrates that Egypt is centrally located in a region with the highest prevalence of the p.Gly2019Ser mutation globally. The map's arrows depict potential migration routes through which this mutation could have been introduced to Egypt. We speculate that the p.Gly2019Ser mutation might have been brought to Egypt via east-west migration during the movements of Islamic Arab and North African Berbers, known as the Maghrebi Effect (red arrow), or through maritime invasion and trades activities across the Mediterranean involving the Byzantines, Vandals, Romans, Greeks, and Phoenicians (orange, blue, yellow, grey, and green arrows), known as the \"back to Africa\" gene flow.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4456878/v1/82ca75b3385596e408ea2ffc.png"},{"id":68431709,"identity":"47b84442-3dbe-4672-aa0a-0424d7d0b220","added_by":"auto","created_at":"2024-11-07 08:07:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2310920,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4456878/v1/9d0cf719-1cbd-4dd2-9eac-ce04bd8f2c03.pdf"},{"id":59434188,"identity":"c456f9d1-5565-489b-b216-4eddbbb332b3","added_by":"auto","created_at":"2024-07-01 18:57:22","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1179784,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementarytableandFigure.docx","url":"https://assets-eu.researchsquare.com/files/rs-4456878/v1/3c9e9e9355d9041098802db1.docx"}],"financialInterests":"(Not answered)","formattedTitle":"The p.Gly2019Ser is the commonest pathogenic mutation in the LRRK2 gene among Egyptians with familial and sporadic Parkinson's disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eParkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms such as tremors, stiffness, and bradykinesia, in addition to other non-motor symptoms including anxiety, depression, constipation, and orthostatic hypotension. While aging is the primary risk factor for PD, research suggests a significant influence of genetic and environmental factors in the development of the disease \u003csup\u003e1,2\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn the past two decades, advances in genetics have greatly enhanced our understanding of the molecular mechanisms leading to the development of PD \u003csup\u003e3,4\u003c/sup\u003e. One promising area of PD research is the role of the LRRK2 protein and its enzymatic activity. PD related pathogenic mutations in \u003cem\u003eLRRK2\u003c/em\u003e gene can increase this activity, making it an attractive target for novel neuroprotective drugs with kinase inhibitors potentials \u003csup\u003e5\u0026ndash;7\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo date, there have been extensive studies on various PD related \u003cem\u003eLRRK2\u003c/em\u003e variants, with at least 20 classifieds as \"pathogenic,\" and others considered likely pathogenic or of uncertain significance \u003csup\u003e5,8\u003c/sup\u003e. It is widely recognized that \u003cem\u003eLRRK2\u003c/em\u003e variants linked to PD exhibit diverse geographic and ancestral distributions \u003csup\u003e8,9\u003c/sup\u003e. For instance, the well-known p.Gly2019Ser mutation has a higher prevalence in PD patients from North African and Ashkenazi Jewish backgrounds compared to individuals of European ancestry \u003csup\u003e10\u003c/sup\u003e. The p.Arg1441Gly mutation, on the other hand, is notably common in the Basque population, contributing to almost half of familial PD cases in that region \u003csup\u003e11\u003c/sup\u003e. Variants like p.Gly2385Arg and p.Arg1628Pro are more frequently observed in PD patients of East Asian descent \u003csup\u003e9,12\u003c/sup\u003e. The pathogenic variant p.Asn1437Ser is mainly found in Germans, while p.Asn1437His is more prevalent in Scandinavians, and p.Asn1437Asp is common in the Chinese population \u003csup\u003e13\u003c/sup\u003e. Other few rare \u003cem\u003eLRRK2\u003c/em\u003e mutations were exclusively found in specific families such as the p.Tyr1699Cys variant was observed in a German Canadian family \u003csup\u003e14\u003c/sup\u003e, and the p.Ile2020Thr mutation was detected in a Japanese family with a single-founder effect \u003csup\u003e15\u003c/sup\u003e. Notably, to date no disease-causing \u003cem\u003eLRRK2\u003c/em\u003e PD mutation was reported in individuals of sub-Saharan African descent.\u003c/p\u003e \u003cp\u003eKnowledge about the prevalence of the pathogenic \u003cem\u003eLRRK2\u003c/em\u003e variants in Egyptians is lacking. To date only three studies are available with a limited number of patients included. Hashad and colleagues \u003csup\u003e16\u003c/sup\u003e examined the prevalence of \u003cem\u003eLRRK2\u003c/em\u003e p.Gly2019Ser mutation in a cohort of 113 Egyptian patients with sporadic PD and 87 healthy controls from lower Egypt, specifically Alexandria and nearby regions. Of the PD patients, 11 individuals (9.7%) tested positive for the p.Gly2019Ser mutation, all of whom were heterozygous. None of the individuals in the control group had the mutation. El Desoky et al \u003csup\u003e17\u003c/sup\u003e assessed the \u003cem\u003eLRRK2\u003c/em\u003e p.Gly2019Ser in 69 individuals with sporadic PD and 96 matched controls from Assiut Governorate and nearby regions in upper Egypt. Out of the 69 PD patients, only one individual (1.45%) was found to be a heterozygous carrier of the p.Gly2019Ser mutation. None of the other participants, both patients and controls, had the mutation. The authors hypothesized that the prevalence of p.Gly2019Ser is lower among Egyptians residing in Upper Egypt compared to those living in North Egypt. However, they concluded that a multicenter study should be conducted on a larger cohort of Egyptians with PD to accurately determine the prevalence of the p.Gly2019Ser mutation. Lastly, Shan \u0026amp; Wszolek\u003csup\u003e18\u003c/sup\u003e reported on the first case of familial PD in an Egyptian family caused by the \u003cem\u003eLRRK2\u003c/em\u003e Arg1441Cys mutation. The proband is a male patient, aged 57, with two affected parents. He experienced his first symptoms when he was 49 years old and presented with a unilateral typical akinetic-rigid syndrome which responded well to carbidopa/levodopa therapy.\u003c/p\u003e \u003cp\u003eSituated at the crossroads of Africa, the Middle East, and Europe, Egypt possesses distinctive characteristics in terms of geography, geopolitics, and history. Egypt's unique location has played a role in shaping the genetic composition of its people through historical invasion and migratory events. The modern-day Egyptians represent a homogeneous population with exclusive genetic variants and unique genetic admixture from Europeans, Arabs, Asians, and Africans ancestries \u003csup\u003e19\u003c/sup\u003e. Egypt, with a population of over 110\u0026nbsp;million, is the fourteenth most populous country in the world and the third most populous country in Africa \u003csup\u003e20\u003c/sup\u003e. As the number of elderly individuals in Egypt increases and life expectancy rises, it is expected that there will be a significant increase in the number of people developing neurodegenerative disorders such as PD \u003csup\u003e21\u003c/sup\u003e. Although exact statistics are not readily available, the limited information suggests that the prevalence of PD in Egypt could be around 500 cases per 100,000 individuals, which is among the highest rates globally \u003csup\u003e22,23\u003c/sup\u003e. To ensure that this expanding and ancestrally distinct patient population can take advantage of the progress being made in the diagnosis and treatment of PD, it is crucial to comprehensively examine their genetic makeup and risk to the disease.\u003c/p\u003e \u003cp\u003eThe International Parkinson\u0026rsquo;s Disease Genomic Consortium Africa (IPDGC Africa), a consortium dedicated to advancing the understanding of PD in Africans \u003csup\u003e24\u003c/sup\u003e, has previously investigated the PD genetic risks associated with \u003cem\u003eLRRK2\u003c/em\u003e in a large cohort of Nigerians from sub-Saharan Africa \u003csup\u003e25,26\u003c/sup\u003e. The current report showcases the progress of this consortium and presents the findings from the second cohort of its members in Egypt and represents the most extensive and thorough investigation of \u003cem\u003eLRRK2\u003c/em\u003e PD related variants conducted in Egyptians to date.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment and cohort\u0026rsquo;s characteristics\u003c/h2\u003e \u003cp\u003eA total of 1,210 participants were included in this study: 611 patients with PD (64.8% male) and 599 unrelated healthy controls (43.4% male). The recruitment process took place in 16 governorates, covering 90% of the inhabited regions, across Egypt: 12 in lower Egypt and 4 in upper Egypt. All participants self-identified as native Egyptians for at least two generations. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the distribution of recruitment sites throughout Egypt and the number of participants (cases and controls) recruited at each site. Notably, approximately 70% of the cohort participants (PD 422, Controls 422) were recruited from lower Egypt, while 30% of the participants (PD 189, Controls 177) were from upper Egypt.\u003c/p\u003e \u003cp\u003eThe mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD age of PD patients at recruitment was 61.01\u0026thinsp;\u0026plusmn;\u0026thinsp;9.67 years (range: 31\u0026ndash;94), while the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD age at recruitment of controls was 43\u0026thinsp;\u0026plusmn;\u0026thinsp;14 years (range: 17\u0026ndash;90). Among PD patients, 4.91% (30/611) had their first symptoms before 40, and 24.55% (150/611) developed PD before turning 50. Family history of PD was identified in 11.46% (70/611) of patients. Consanguinity was uncommon, present in only 3.6% of the patients' families. The mean age at diagnosis was 54.33\u0026thinsp;\u0026plusmn;\u0026thinsp;8.68 years (range 21\u0026ndash;83), which aligns with the mean age at onset of initial motor symptoms at 53.81\u0026thinsp;\u0026plusmn;\u0026thinsp;8.56 years (range 21\u0026ndash;83). The mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD MDS Unified Parkinson's Disease Rating Scale (UPDRS) score for patients was 100.35\u0026thinsp;\u0026plusmn;\u0026thinsp;49.96 (range: 7-231). Supplementary table 1 lists the demographic and UPDRS scores of the study participants and compare these characteristics between individuals from lower and upper Egypt. Except for the age of the patients during the study, duration of illness and the MDS UPDRS scores at the time of study, there were no significant differences observed between PD patients from upper and lower Egypt. At the time of the study, patients from Upper Egypt were, on average, approximately 2 years younger than those from Lower Egypt. Additionally, the duration of their illness was, on average, 3 years shorter, and their UPDRS scores were about 10 points higher compared to patients from Lower Egypt (P value\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Notably, there were no significant differences in the age of onset between the two groups (Upper Egypt 53.66\u0026thinsp;\u0026plusmn;\u0026thinsp;8.13 years (range 27\u0026ndash;83), Lower Egypt 53.88\u0026thinsp;\u0026plusmn;\u0026thinsp;8.71 years (21\u0026ndash;79): U 38971.50, p value 0.652)\u003c/p\u003e \u003cp\u003e \u003cb\u003eLRRK2\u003c/b\u003e \u003cb\u003epathogenic SNPs in patients and controls\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA validated allele Specific fluorescence-based PCR assays (KASP assays) were used to genotype 12 pathogenic \u003cem\u003eLRRK2\u003c/em\u003e SNPs. The assay performed effectively and clearly distinguished genotyping clusters for all 12 SNPs. The allelic frequencies for all SNPs were in Hardy-Weinberg equilibrium (p\u0026thinsp;=\u0026thinsp;0.88-1).\u003c/p\u003e \u003cp\u003eIn both the PD patients and controls, only the p.Gly2019Ser mutation was detected, while the other 11 \u003cem\u003eLRRK2\u003c/em\u003e pathogenic variants were not found. A summary of the genotyping results for the 12 \u003cem\u003eLRRK2\u003c/em\u003e SNPs is provided in Supplementary Table\u0026nbsp;2.\u003c/p\u003e \u003cp\u003eAmong the participants who were successfully genotyped for p.Gly2019Ser, 4.38% (24/547) of PD patients and 0.68% (4/587) of healthy controls were found to carry the pathogenic p.Gly2019Ser allele. As expected, the p.Gly2019Ser is significantly associated with PD status (OR 6.688, 95% CI 2.305\u0026ndash;19.403, p-value 0.0001). The p.Gly2019Ser Minor Allelic Frequencies distribution in patients (MAF\u0026thinsp;~\u0026thinsp;0.023) and in controls (MAF\u0026thinsp;~\u0026thinsp;0.003) were uniform across Egypt with no significant differences observed between upper and lower regions (\u003cem\u003eX\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e 0.1367, p-value: 0.71). The carrier rate was 6.45% (4/62) in familial PD cases and 4.12% (20/485) in non-familial cases. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e details the Genotypic and Allelic frequencies of the p.Gly2019Ser in this cohort, including a breakdown of its distribution in upper and lower Egypt.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGenotypic and allelic frequencies of the \u003cem\u003eLRRK2\u003c/em\u003e p.Gly2019Ser in carriers vs noncarriers\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eRegion\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e\u003cem\u003eGenotype frequencies\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e\u003cem\u003eAllele frequencies\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eAcross Egypt\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll Cases (547)\u003c/p\u003e \u003cp\u003eFamilial (62)\u003c/p\u003e \u003cp\u003eSporadic (485)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e523 (0.956)\u003c/p\u003e \u003cp\u003e58 (0.935)\u003c/p\u003e \u003cp\u003e465 (0.959)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (0.042)\u003c/p\u003e \u003cp\u003e3 (0.048)\u003c/p\u003e \u003cp\u003e20 (0.041)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.002)\u003c/p\u003e \u003cp\u003e1 (0.016)\u003c/p\u003e \u003cp\u003e0 (0.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1069 (0.977)\u003c/p\u003e \u003cp\u003e119 (0.960)\u003c/p\u003e \u003cp\u003e950 (0.979)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25 (0.023)\u003c/p\u003e \u003cp\u003e5 (0.040)\u003c/p\u003e \u003cp\u003e20 (0.021)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControls (587)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e583 (0.993)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (0.007)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1170 (0.997)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4 \u0026nbsp; (0.003)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eUpper Egypt\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCases (186)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e177 (0.952)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (0.048)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e363 (0.976)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9 (0.024)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControls (177)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176 (0.994)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.006)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e353 (0.997)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (0.003)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eLower Egypt\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCases (361)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e346 (0.958)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (0.039)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.003)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e706 (0.978)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16 (0.022)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControls (410)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e407 (0.993)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (0.007)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e817 (0.996)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (0.004)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDemographic, clinical characteristics and haplotype of the p.Gly2019Ser carriers\u003c/h2\u003e \u003cp\u003eAmong the 24 PD patients with the p.Gly2019Ser mutation, 15 were recruited from Lower Egypt and 9 were from Upper Egypt, with a male predominance of 70.83%. The average age at recruitment of these patients was 59.67\u0026thinsp;\u0026plusmn;\u0026thinsp;8.32 years (range:42\u0026ndash;79), while the mean age of disease onset was 52\u0026thinsp;\u0026plusmn;\u0026thinsp;8.07 years (range: 38\u0026ndash;67). Most patients (79.17%) developed their first motor symptoms before the age of 60, with 4.17% experiencing symptoms before 40, 20.83% between 40 and 49, 45.83% between 50 and 59, and 20.83% between 60 and 69 years. Only 16% had a family history of PD, while 84% were sporadic cases. Consanguinity within the family was reported only in 4.17% (1/24). The Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD of MDS-UPDRS score for p.Gly2019Ser carriers with PD was 120.48\u0026thinsp;\u0026plusmn;\u0026thinsp;59.61. There were no significant differences in demographic characteristics or UPDRS scores between p.Gly2019Ser PD carriers and non-carriers (see Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical characteristics of p.Gly2019Ser carriers vs non-carriers\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eParameter\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNon-G2019S carriers (n\u0026thinsp;=\u0026thinsp;523)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eG2019S carriers (n\u0026thinsp;=\u0026thinsp;24)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP-value\u003c/em\u003e\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender distribution, n (%)\u003c/p\u003e \u003cp\u003eFemale\u003c/p\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e183 (34.99)\u003c/p\u003e \u003cp\u003e340 (65.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (29.17)\u003c/p\u003e \u003cp\u003e17 (70.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.664\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at Study (y),mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.69\u0026thinsp;\u0026plusmn;\u0026thinsp;9.79 (31\u0026ndash;94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59.67\u0026thinsp;\u0026plusmn;\u0026thinsp;8.32 (42\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.523\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at onset (y), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53.82\u0026thinsp;\u0026plusmn;\u0026thinsp;8.67 (21\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52\u0026thinsp;\u0026plusmn;\u0026thinsp;8.07 (38\u0026ndash;67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.377\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYoung onset PD (\u0026lt;\u0026thinsp;40 y), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (5.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.9999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEarly onset PD (\u0026lt;\u0026thinsp;50 y), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e129 (24.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (33.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.340\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at Diagnosis (y), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54.28\u0026thinsp;\u0026plusmn;\u0026thinsp;8.77 (21\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52\u0026thinsp;\u0026plusmn;\u0026thinsp;8.07 (38\u0026ndash;67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.246\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily History n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (11.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (16.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.336\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of illness, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.88\u0026thinsp;\u0026plusmn;\u0026thinsp;5.47 (0\u0026ndash;33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.67\u0026thinsp;\u0026plusmn;\u0026thinsp;5.90 (0\u0026ndash;25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.393\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMDS UPDRS mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e118.83\u0026thinsp;\u0026plusmn;\u0026thinsp;48.94 (7-223)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120.48\u0026thinsp;\u0026plusmn;\u0026thinsp;59.61 (38\u0026ndash;231)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.151\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e* P values for categorical variables were calculated using Fisher's exact test and for continuous variables using the Mann-Whitney U test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe Four non-manifesting p.Gly2019Ser carriers in the control group were two females aged 26 and 29, and one male aged 55 from lower Egypt and one female aged 39, from upper Egypt. None of the control carriers reported a family history of PD. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e details the characteristics and UPDRS scores of each of the 28 individuals (24 patients and 4 controls) who are positive for the p.Gly2019Ser pathogenic variant. This patient, a male from Upper Egypt, had a family history of PD on both parents. He first exhibited motor symptoms at 45 and initially responded well to levodopa therapy. However, his progressively worsened, and by the age of 54, when he joined the study, he began experiencing dyskinesia and rapid wearing-off effects.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIndividual demographics and UPDRS scores of p.Gly2019Ser carriers\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhenotype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRegion\u003c/p\u003e \u003cp\u003e% from total\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGovernorate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAge (y)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003cp\u003eat\u003c/p\u003e \u003cp\u003eonset (y)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFamily History\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eConsanguinity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eUPDRS score\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"14\" rowspan=\"15\"\u003e \u003cp\u003eLower Egypt\u003c/p\u003e \u003cp\u003e4.15% (15/361)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCairo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e139\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCairo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e230\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGiza\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e163\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGiza\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGiza\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e231\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eQalyubia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCairo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCairo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMansoura\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e223\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMansoura\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e194\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBanha\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCairo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAlexandria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eUnavailable\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAlexandria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAlexandria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"8\" rowspan=\"9\"\u003e \u003cp\u003eUpper Egypt\u003c/p\u003e \u003cp\u003e4.84% (9/186)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAsyut\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAsyut\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAsyut\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAsyut\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAsyut\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e171\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAsyut\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e128\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAsyut\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e153\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAsyut\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e119\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAsyut\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSummary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMales (70.83%)\u003c/p\u003e \u003cp\u003eFemales\u003c/p\u003e \u003cp\u003e(29.17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e59.67\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;8.32\u003c/p\u003e \u003cp\u003e(42\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e52.00\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;8.07\u003c/p\u003e \u003cp\u003e(38\u0026ndash;67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e(16.67%)\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003e(83.33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1/24\u003c/p\u003e \u003cp\u003e(4.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e120.48\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;59.61\u003c/p\u003e \u003cp\u003e(38\u0026ndash;231)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eLower Egypt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCairo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGiza\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCairo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUpper Egypt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAsyut\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAll p.Gly2019Ser carriers (except for one control sample that failed during genotyping) had at least one copy of the minor allele (A) of the rs28903073 SNP, suggesting they shared haplotype 1. This haplotype is widely recognized as the predominant haplotype for the p.Gly2019Ser mutation, commonly encountered in individuals carrying the p.Gly2019Ser pathogenic allele across Europe, North and South America, as well as North Africa \u003csup\u003e45\u003c/sup\u003e. Supplementary Fig.\u0026nbsp;1 illustrates the Sanger sequencing chromatograms of the rs28903073 SNP in individuals carrying the p.Gly2019Ser variant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIt has been more than twenty years since the identification of \u003cem\u003eLRRK2\u003c/em\u003e as a genetic factor associated with both familial and sporadic PD \u003csup\u003e27,28\u003c/sup\u003e. Situated on chromosome 12, \u003cem\u003eLRRK2\u003c/em\u003e is among the most researched genes in PD. It consists of 51 exons spanning 144 kb and encodes a large 286 kDa multidomain protein of the same name. Over 300 genetic variants have been identified in \u003cem\u003eLRRK2\u003c/em\u003e, with at least 20 variants confirmed as pathogenic. These variations follow an autosomal dominant inheritance pattern and are primarily located in LRRK2\u0026rsquo;s catalytic core, which includes the ROC, COR, and Kinase domains. They result in enhanced LRRK2 autophosphorylation activity and increased phosphorylation of surrogate substrates, leading to a harmful kinase gain of function \u003csup\u003e5,13,29\u003c/sup\u003e. Inhibitors that control the activity of the LRRK2 kinase are among the most promising new drug targets for PD currently undergoing clinical trials \u003csup\u003e5\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe existing understanding of the genetic risk of PD in the Middle East and North Africa (MENA), particularly in Egypt, the most populous country in this region, is limited and relies mainly on preliminary data from case reports and small cohorts \u003csup\u003e16\u0026ndash;18,30\u003c/sup\u003e. In this study our consortium reports on the largest multicenter investigation in Egyptians with PD to date. The study examined the prevalence of 12 \u003cem\u003eLRRK2\u003c/em\u003e variants with confirmed pathogenicity including the p.Gly2019Ser, among 611 PD patients and 599 controls from 16 out of Egypt's 27 governorates, encompassing around 90% of the nation's populated regions.\u003c/p\u003e \u003cp\u003eThe p.Gly2019Ser mutation was the only \u003cem\u003eLRRK2\u003c/em\u003e variant found in this cohort. None of the other 11 variants were detected. Carriers of the p.Gly2019Ser pathogenic allele were found across upper and lower Egypt, with a combined average prevalence of 4.4% (MAF 2.3%) among PD patients. This prevalence was higher in familial cases (6.4%) compared to sporadic patients (4.1%) and did not show significant variability between upper and lower regions. These results affirm the p.Gly2019Ser mutation as the most prevalent \u003cem\u003eLRRK2\u003c/em\u003e risk variant in Egyptians with PD, known to date. In addition, they suggest a widespread distribution of this mutation across the entire country, including Upper Egypt, contrary to previous reports that had localized its presence to Lower Egypt \u003csup\u003e16,17\u003c/sup\u003e. While the 4.4% prevalence rate of the p.Gly2019Ser variant in our cohort is below the 9.7% reported previously by Hashad et al. \u003csup\u003e16\u003c/sup\u003e, this figure still ranks among the highest ranges reported worldwide. It is noteworthy that the study conducted by Hashed et al has a significantly smaller sample size compared to our cohort and was limited to a single governorate in lower Egypt. Most PD patients carrying the p.Gly2019Ser mutation in our study developed symptoms in their forties and fifties. There were no significant variations in the age of onset, male predominance, or total UPDRS scores between those with and without the p.Gly2019Ser mutation.\u003c/p\u003e \u003cp\u003eIt is worth noting that the p. Gly2019Ser mutation was also identified among the control group at an average prevalence of 0.68% (MAF 0.3%). This figure again ranks among the highest reported rates in controls globally and is like those found in non-manifesting carriers within the Maghrib (0.7-2%) and Ashkenazi Jewish (0.4-2%) populations. Although two non-manifesting carriers are under 30 and might develop PD later in life, the presence of the p.Gly2019Ser mutation in two unaffected controls aged 39 and 55 indicates a reduced or incomplete penetrance of this variant in Egypt. Penetrance, which refers to the likelihood of an individual with the mutation developing PD by a specific age, exhibits a wide range of estimates for the p. Gly2019Ser mutation, ranging from 7\u0026ndash;100% \u003csup\u003e31\u0026ndash;33\u003c/sup\u003e. Factors such as ethnicity, gender, and the interplay of genetic and environmental factors can influence these penetrance rates \u003csup\u003e34\u003c/sup\u003e. Additional research, including longitudinal and familial studies, are necessary to determine the penetrance rates of the p.Gly2019Ser mutation in Egyptians and to identify factors that might modify this penetrance.\u003c/p\u003e \u003cp\u003eAn important observation in this study is that around one quarter of PD patients who did not have the p.Gly2019Ser mutation experienced symptoms before turning 50 years old. This percentage exceeds the global Early Onset Parkinson\u0026rsquo;s Disease (EOPD) rates of 3\u0026ndash;14% and aligns closely with data from previous clinical and epidemiological studies on EOPD in Egypt \u003csup\u003e23,35,36\u003c/sup\u003e. Interestingly, the incidence of a family history of PD was relatively low, around 16% in p.Gly2019Ser carriers and 11% in non-carriers. consistent as well with previously reported rates in Egyptians (11\u0026ndash;15%)\u003csup\u003e37,38\u003c/sup\u003e. Furthermore, the consanguinity rates among families of PD patients were below 5% in all regions. The coexistence of high EOPD rates and lack of family history of PD and (or) consanguinity in Egyptian patients present an intriguing scenario. EOPD is typically associated with higher genetic risks and tends to be hereditary\u003csup\u003e3,39\u003c/sup\u003e. Combining these observations with the fact that only 5% of EOPD cases in the cohort could be attributed to the LRRK2 p.Gly2019Ser mutation suggests that other genetic variants may be involved in the development of Parkinson's Disease (PD) among Egyptians\u003csup\u003e40\u003c/sup\u003e. We speculate that these variants are likely to be either recessive or arise as de novo mutations. Nonetheless, the absence of substantial familial rates hints at potential contributions of environmental factors as well \u003csup\u003e40\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSince the discovery of the p. Gly2019Ser mutation, numerous studies have investigated its date and origin in different populations, linking it to three distinct haplotypes identified as haplotype 1, 2, and 3 \u003csup\u003e41\u003c/sup\u003e. Haplotype 1 is particularly prevalent among carriers of the mutation worldwide, identified in Europeans, Ashkenazi Jews, North Africans, and Latin Americans \u003csup\u003e42\u003c/sup\u003e. Haplotype 2 is present in individuals of European descent, while Haplotype 3 was first observed in Turkish and Japanese families. Haplotypes 2 and 3 are both extremely rare, less studied and seem to have emerged more recently compared to Haplotype 1 \u003csup\u003e41\u003c/sup\u003e. Within our cohort, all individuals with the p.Gly2019Ser mutation shared Haplotype 1, suggesting a common ancestral founder with most carriers of the mutation in other populations.\u003c/p\u003e \u003cp\u003eIn the field of population genetics, it is commonly believed that the central point of origin for a mutation corresponds with where the mutation is most prevalent \u003csup\u003e43\u003c/sup\u003e. It is hypothesized that the founding event of the p.Gly2019Ser mutation likely occurred in the Near East about 4000\u0026ndash;5000 years ago before spreading to Europe and other regions due to migratory movements \u003csup\u003e41,44,45\u003c/sup\u003e. Egypt is located at a critical juncture for historical migratory paths through which the p.Gly2019Ser could have been introduced to its population To the west, Egypt shares borders with Maghreb countries where the mutation is prevalent, particularly among Arab barbers, with rates of 39% in sporadic PD and 36% in familial PD cases \u003csup\u003e8\u003c/sup\u003e. In the east, the prevalence of the mutation is approximately 10.6% in sporadic PD cases and 26% in familial cases among Ashkenazi Jews, making them the second most affected ethnic group. Southern Mediterranean European countries exhibit higher frequencies of the mutation (2\u0026thinsp;\u0026minus;\u0026thinsp;4% in sporadic PD and 3\u0026thinsp;\u0026minus;\u0026thinsp;14% in familial PD) compared to Northern European nations (\u0026lt;\u0026thinsp;1\u0026thinsp;\u0026minus;\u0026thinsp;2% in sporadic PD and 0\u0026thinsp;\u0026minus;\u0026thinsp;3% in familial PD) \u003csup\u003e8\u003c/sup\u003e. Notably, the p.Gly2019Ser mutation is rare in Asian countries and absent in Sub-Saharan Africa \u003csup\u003e25,26\u003c/sup\u003e. It is plausible that the p.Gly2019Ser entered Egypt via the east-west axis during the migratory movements of Arab and (or) North African Berbers (referred to as the Maghrebi Effect) or through north-south axis by the maritime migrations across the Mediterranean, known as the \"back to Africa\" gene flow (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). \u003csup\u003e46,47\u003c/sup\u003e. To fully identify the origin and transmission path of this mutation into Egypt and its environs, it is crucial to explore the genetic ancestries and migratory events within this population and adjacent nations.\u003c/p\u003e \u003cp\u003eIn conclusion, this study provides insight from the most extensive genetic investigation carried out on PD susceptibility in Egyptians to date. It verifies the high prevalence rates of the p.Gly2019Ser mutation in Egypt which are similar to the rates seen in Southern Mediterranean areas. Significantly, it confirms the presence of the p.Gly2019Ser mutation in individuals indigenous to upper Egypt. These findings place Egyptians at the forefront of populations that may be able to host and benefit from \u003cem\u003eLRRK2\u003c/em\u003e therapeutic programs that are presently in progress.\u003c/p\u003e \u003cp\u003eHowever, our study raises several unresolved questions particularly regarding the penetrance rates and the route of entry of the p.Gly2019Ser mutation into Egypt. Moreover, the lack of clinical scales within this cohort has impeded the comprehension of clinical characteristics of patients including the understanding of both motor and non-motor symptoms, disease progression, and the efficacy of antiparkinsonian medications. Efforts are underway within our team to gather additional data to address these limitations. It is important to highlight as well that this study focused on assessing only 12 \u003cem\u003eLRRK2\u003c/em\u003e variants using a targeted approach. A more comprehensive analysis utilizing untargeted next generation whole exomes and whole genome sequencing methods are necessary in this population to investigate both known and novel PD variants, especially in cases of EOPD.\u003c/p\u003e \u003cp\u003eFinally, we hope that our study will encourage further investigations on \u003cem\u003eLRRK2\u003c/em\u003e in the adjacent territories including the Levant, the Arabian Peninsula, and the Nile basin. It will be of interest to explore if the p.Gly2019Ser mutation presence extends beyond lower Egypt into countries that have had historical migratory links with Egypt, such as Sudan, Ethiopia, Oman, and Yemen. The exploration of the mutation's distributions in these regions poses an interesting question that warrants deeper exploration.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eParticipants recruitment\u003c/h2\u003e \u003cp\u003e The study was granted ethical approval by the Egyptian participating institutions review boards (Ethics Approval # 2021-2022-058 and 2021-2022-203), as well as University College London (UCL) ethical committee (REC # 22/NE/0080). Written informed consent was obtained from all participants at each study site in accordance with the Declaration of Helsinki and the Common Rule.\u003c/p\u003e \u003cp\u003eOne thousand two hundred and ten Egyptians, including 611 PD patients and 599 unrelated healthy controls, were recruited by the IPDGC Africa members through two established networks in Egypt. Specifically, 479 PD patients and 481 unrelated controls were recruited through the Egyptian Network of Neurodegenerative Diseases (ENND), which is a pan Egypt network formed in December 2013 and is based in multiple universities including Mansoura, Cairo, Ain-Shams, Al-Azhar, Alexandria, Assiut, Tanta, Zagazig, Menoufia, Sohag, Al-Minya, Banha, Suez Canal Universities, and The American University in Cairo. An additional 132 PD patients and 118 controls were included from an independent cohort from the University of Assiut. The recruitment process took place between 2011 and 2022. Only subjects who self-declared themselves and their both parents as native Egyptians were included in the study.\u003c/p\u003e \u003cp\u003ePD patients were diagnosed by movement disorders specialists using the UK Brain Bank Criteria \u003csup\u003e48\u003c/sup\u003e and (or) the criteria established by the Movement Disorder Society Task Force \u003csup\u003e49\u003c/sup\u003e. Controls were unrelated-healthy individuals who do not have a history of PD or any other neurological condition. Basic demographic information including age, gender, self-declared ethnicity, age at disease onset (defined as age at experiencing first motor symptoms), and age at diagnosis (for cases only), were collected from all participants. The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) were also collected from patients.\u003c/p\u003e \u003cp\u003e \u003cb\u003eLRRK2\u003c/b\u003e \u003cb\u003eSNPs Genotyping\u003c/b\u003e\u003c/p\u003e \u003cp\u003eDNA was extracted from either 10 mL of venous whole blood samples or saliva samples using established protocols. Genotyping was carried out using the Kompetitive Allele Specific Polymerase Chain Reaction assay (KASP; LGC Genomics, Herts, UK) as described previously \u003csup\u003e25\u003c/sup\u003e. Twelve \u003cem\u003eLRRK2\u003c/em\u003e single-nucleotide polymorphisms (SNPs) were selected for genotyping. These SNPs include rs34637584 (p.Gly2019Ser), rs34995376 (p.Arg1441His), rs74163686 (p.Asn1437His), rs35870237 (p.Ile2020Thr), rs35801418 (p.Tyr1699Cys), rs34410987 (p.Pro755-Leu), rs34778348 (p.Gly2385Arg), rs281865052 (p.Met1869Val), rs34594498 (p.Ala419Val), rs33949390 (p.Arg1628Pro), rs35808389 (p.Leu1114Leu), and rs34805604 (p.Ile1122Val). These SNPs were carefully chosen based on strict criteria, including replicated association studies, robust disease segregation data, functional evidence, and the availability of a validated KASP assay for each SNP. To ensure the pathogenicity of each SNP, we checked the ClinVar and MDS Gene databases \u003csup\u003e50,51\u003c/sup\u003e. Initially, we also included the SNP rs33939927, which codes for p.Arg1441Gly/Cys/Ser. However, we later determined that it was unsuitable for KASP genotyping due to its proximity to rs34995376 (p.Arg1441His) and its tri-allelic nature.\u003c/p\u003e \u003cp\u003eThe haplotype background for p.Gly2019Ser carriers was determined by genotyping the rs28903073. The “A” allele for this SNP has a frequency of \u0026lt; 0.1% and if observed indicates the presence of haplotype 1 \u003csup\u003e45\u003c/sup\u003e. Variant specific primer was designed using primer 3 software (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://bioinfo.ut.ee/primer3-0.4.0\u003c/span\u003e\u003cspan address=\"http://bioinfo.ut.ee/primer3-0.4.0\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). PCR was performed using Touchdown with the following cycling conditions: 94°C for 10 minutes; 8 cycles of [30 seconds at 94°C, 30 seconds at 65°C, 45 seconds at 72°C]; 18 cycles of [30 seconds at 94°C, 30 seconds at (65 − 55°C), 45 seconds at 72°C]; 14 cycles of [30 seconds at 94°C, 30 seconds at 55°C, 45 seconds at 72°C; and a final extension step of 10 minutes at 72°C. SNP genotyping was performed using standard bi-directional Sanger sequencing.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData summaries and statistical analysis\u003c/h2\u003e \u003cp\u003eThe cohort's demographics and clinical characteristics were summarized using appropriate descriptors including mean and standard deviation (SD) for continuous variables and percent frequency for categorical variables and compared between groups (PD and controls) using two-tailed χ2 test for categorical variables or non-parametric alternative for continuous variables as relevant. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) Statistics for Windows, version 29.0 (IBM Corp, Armonk, NY, USA). The genotyping data for SNPs were analyzed using SNP Viewer software (version 1.99; Hoddesdon, UK) and tested for Hardy-Weinberg equilibrium using the χ2 test. Results of the sanger sequencing were analyzed using SEQUENCHER (Version 5.4.5, Gene Codes Corporation, Inc).\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eData access\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eAnonymized genotyping and clinical data can be provided to \u003cem\u003ebone fide\u003c/em\u003e researchers upon request from the corresponding author(s).\u003c/p\u003e \u003cp\u003e\u003c/p\u003e \u003c/div\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization and design: Mie Rizig and Mohamed Salama\u003c/p\u003e\n\u003cp\u003eData acquisition: All authors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDrafting of manuscript:\u0026nbsp;Martina B. William\u003csup\u003e\u0026nbsp;\u003c/sup\u003eand Mie Rizig.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCritical revision of manuscript for intellectual content: All authors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStatistical analysis:\u0026nbsp;Martina B. William, Mohamed H. Yousef,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eand Mie Rizig.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdministrative, technical, or material support: Mie Rizig and Mohamed Salama\u003c/p\u003e\n\u003cp\u003eSupervision of genotyping: Mie Rizig and Mohamed Salama\u003c/p\u003e\n\u003cp\u003eData management: Mie Rizig and Mohamed Salama\u003c/p\u003e\n\u003cp\u003eFunding acquisition: Mie Rizig, Henry Houlden, and Mohamed Salama\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eWe would like to thank the patients, their care partners, and the controls for their participation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial Disclosure:\u0026nbsp;\u003c/strong\u003eMie Rizig received funding from the University College London Grand Challenges Small Grants (Award ID:177813), the\u0026nbsp;MRC neurosciences and mental health research grant. April 2023 \u0026ndash; April 2026 and The Michael J Fox Foundation Genetic Diversity in Parkinson\u0026rsquo;s Disease 2019 (Grant ID:17483). Henry Houlden received funding from the Michael J Fox Foundation Genetic Diversity in Parkinson\u0026rsquo;s Disease (Grant ID: 17483).\u0026nbsp;Mohamed Salama\u0026nbsp;received funding from\u0026nbsp;the Bartlett Fund for Critical Challenges- 2021 (Agreement Number: 2 \u0026ndash; Cycle 3) and the American University in Cairo Faculty Support Grant-2021 awarded to. The funders were not involved in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u0026nbsp;\u003c/strong\u003eAll authors declare no conflict of interest.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSakowski, S. A., Koubek, E. J., Chen, K. S., Goutman, S. A. \u0026amp; Feldman, E. L. 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Gly2019Ser","lastPublishedDoi":"10.21203/rs.3.rs-4456878/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4456878/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe impact of \u003cem\u003eLRRK2\u003c/em\u003e variants on the risk of Parkinson's disease (PD) in Egyptians remains unknown. We examined 1,210 Egyptians (611 PD patients and 599 controls) for 12 \u003cem\u003eLRRK2\u003c/em\u003e mutations. The p.Gly2019Ser was the only variant detected across Egypt, with a prevalence of 4.1% in sporadic cases, 6.5% in familial cases, and 0.68% in controls. Among p.Gly2019Ser carriers, all were heterozygous bar one homozygous patient, and all shared the common haplotype 1. Demographics and UPDRS scores did not differ between carriers and non-carriers, with most patients being males and developed PD in their fifties. Early-onset PD prevalence was 33% in carriers and 25% in non-carriers. Familial cases were 16% in carriers and 11% in non-carriers. This study affirms that like other North Africans and Mediterranean populations, Egyptians with PD have a notably high prevalence of the p.Gly2019Ser. \u003cem\u003eLRRK2\u003c/em\u003e inhibitors could be promising therapeutic options for further exploration in this population.\u003c/p\u003e","manuscriptTitle":"The p.Gly2019Ser is the commonest pathogenic mutation in the LRRK2 gene among Egyptians with familial and sporadic Parkinson's disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-01 18:57:17","doi":"10.21203/rs.3.rs-4456878/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-07-04T08:13:08+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-27T12:19:27+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-19T15:35:55+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-18T13:24:43+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-13T17:21:42+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-11T06:11:18+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-10T08:58:22+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-06-10T08:54:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-25T13:15:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-22T10:01:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Parkinson's Disease","date":"2024-05-21T19:54:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-parkinsons-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjparkd","sideBox":"Learn more about [npj Parkinson's Disease](http://www.nature.com/npjparkd/)","snPcode":"41531","submissionUrl":"https://submission.springernature.com/new-submission/41531/3","title":"npj Parkinson's Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"93c9cbed-4c18-4b9a-937f-58759cc6dc09","owner":[],"postedDate":"July 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-07T08:07:16+00:00","versionOfRecord":{"articleIdentity":"rs-4456878","link":"https://doi.org/10.1038/s41531-024-00826-8","journal":{"identity":"npj-parkinsons-disease","isVorOnly":false,"title":"npj Parkinson's Disease"},"publishedOn":"2024-11-06 05:00:00","publishedOnDateReadable":"November 6th, 2024"},"versionCreatedAt":"2024-07-01 18:57:17","video":"","vorDoi":"10.1038/s41531-024-00826-8","vorDoiUrl":"https://doi.org/10.1038/s41531-024-00826-8","workflowStages":[]},"version":"v1","identity":"rs-4456878","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4456878","identity":"rs-4456878","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}