Spinal muscular atrophy genetic epidemiology and the case for premarital genomic screening in Arab populations

Spinal muscular atrophy genetic epidemiology and the case for premarital genomic screening in Arab populations | 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 Spinal muscular atrophy genetic epidemiology and the case for premarital genomic screening in Arab populations Ahmad Abou Tayoun, Fatma Rabea, Maha El Naofal, Ikram Chekroun, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3860416/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Jun, 2024 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Abstract Background Spinal muscular atrophy (SMA) is a fatal autosomal recessive disorder for which several treatment options, including gene therapy, have become available. SMA incidence has not been well-characterized in most Arab countries where rates of consanguinity are high. Understanding SMA disease epidemiology has significant implications for screening, prevention, and treatment in those populations. Methods We preformed SMA diagnostic testing in a clinical multi-national patient cohort (N = 171) referred for hypotonia and/or muscle weakness. In addition, we carried out genetic newborn screening for SMA on 1,252 healthy Emirati newborns to estimate the carrier frequency and incidence of the disease in the United Arab Emirates. Results Patients referred for SMA genetic testing were mostly Arabs (82%) representing 18 countries. The overall diagnostic yield was 33.9%, which was higher (> 50%) for certain nationalities. Most patients (71%) had two SMN2 copies and earlier disease onset. For the first time, we estimate SMA carrier frequency (1.5%) and incidence of the disease (1 in 5,990 live births) in the United Arab Emirates. Using birth and marriage rates in two Arab populations (United Arab Emirates and Saudi Arabia), as well as disease incidence in both countries, we show that, besides preventing new cases, premarital genetic screening could potentially lead to $ 10 to $ 324 million, respectively, annual cost savings relative to postnatal treatment. Conclusion The SMA carrier frequency and incidence we document suggests high potential benefit for universal implementation of premarital genomic screening for a wide range of recessive disorders in Arab populations. Health sciences/Health care/Disease prevention/Preventive medicine Biological sciences/Genetics/Population genetics/Genetic variation Figures Figure 1 Figure 2 Figure 3 Introduction Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder characterized by irreversible loss of alpha motor neurons in the spinal cord and lower brainstem resulting in progressive muscle atrophy and weakness 1 . Its clinical manifestation is highly variable, ranging in onset from intrauterine to adulthood, and in severity from minor muscle weakness to severe paralysis and death. Accordingly, SMA has been classified into four primary subtypes: type I, type II, type III and type IV. Type I, known as infantile SMA, is the most common and severe form of the disease, seen in ~ 50% 2 of affected patients and has an onset before 6 months of age. If untreated, death generally occurs within the first two years of life due to respiratory failure 3 , 4 . SMA is an autosomal recessive disorder caused by biallelic pathogenic variants in the telomeric survival motor neuron 1 ( SMN1 ) gene located on chromosome 5q13 5 . Most affected patients (92%) harbor a homozygous deletion of SMN1 exon 7, while a small subset (4%) are compound heterozygotes for exon 7 deletion on one allele coupled with a small intragenic variant on the other allele 6 . In rare occasions (4%), SMA can be due to over 30 genes identified, other than SMN1 3,6,7 . Though an almost identical homologue to SMN1 , SMN2 can only partially compensate for SMN1 loss. Increase in SMN2 copy number has been associated with milder forms of SMA and, therefore, has prognostic value. Of patients with 4 copies of SMN2 , 1% of patients had SMA type I, 11% had SMA type II and 88% had SMA type III or type IV 4 , 7 . SMA is globally the second most common fatal autosomal recessive disorder. Based on available data in populations of European ancestry, SMA highest incidence and carrier frequency are around 1 in 8000 and 1 in 45, respectively 6 , 7 . These figures are expected to be even higher in regions with high rates of consanguinity, particularly in the Middle East where the incidence has been predicted to range between 10 to 193 in 100,000 live births, almost 40-fold higher than in Western populations 8 . However, there is a lack of data to accurately estimate SMA epidemiology across Arab populations. As such, the primary aim of this study was to estimate the carrier frequency and incidence of SMA in the United Arab Emirates (UAE), and to investigate efficient approaches for disease prevention. Methods Study Design and Participants Clinical Patient Cohort Pediatric patients (age < 18 years old) were referred for diagnostic SMA testing at the Genomics Centre in Al Jalila Childrens’ Specialty Hospital between June 2019 and August 2023. Al Jalila Children’s is the only tertiary pediatric center in the UAE and is the main referral center for pediatric patients with rare diseases across the UAE. Peripheral blood samples were obtained from patients suspected with SMA and clinical data was provided by the referring physician either through the electronic medical record, for internal patients, or on requisition forms, for external patients. The de-identified, reporting of clinical cohort in this study was approved by the Dubai Healthcare Authority Research Ethics Committee (DSREC-07/203_06), which determined that this study meets the exemption criteria with a waiver of informed consent. A subset of this clinical cohort was previously published 9 , though in addition to increasing cohort size, this current study includes additional information on age ranges, diagnostic yield stratified by nationality, and SMN2 copy number status. SMA genetic screening initiative in Emirati Newborn A network of eleven local maternity hospitals across the UAE was established to conduct the country’s first large scale representative genetic newborn screening study for SMA. Recruitment and consenting of Emirati newborns’ (age ≤ 3 months) families were carried out by neonatologists/pediatricians at each hospital. Peripheral blood samples were obtained from each participant and clinical data were provided by the recruiting physician through an electronic collection data sheet. Samples were transported to Al Jalila Genomics Centre where SMA testing was performed. The study was approved by the Dubai Health Authority Scientific Research Ethics Committee (DSREC-06/2021_20), Ministry of Health and Prevention Research Ethics Committee (MOHAP/DXB-REC/SOO/No.81/2021) and Abu Dhabi Health Research and Technology Ethics Committee (DOH/CVDC/2022/1626). DNA Extraction Genomic DNA was extracted from peripheral whole blood using the QIAsymphony DSP DNA Kit (Qiagen, Hilden, Germany) and QIAsymphony automated nucleic acid extraction instrument, according to the manufacturer's instructions. SMA Copy Number Analysis SMN1 and SMN2 copy numbers were determined by Digital droplet PCR (ddPCR) technology using predesigned proprietary ddPCR assay kits for SMN1 (Catalog No: 186–3500, Bio-Rad) and SMN2 (Catalog No: 186–3503, Bio-Rad). The predesigned Bio-Rad assays include reagents to detect both the target gene ( SMN1 or SMN2 ) and an internal reference gene ( RPP30 ). In addition, experimental controls – 0 copy, 1 copy and 2 copy controls for SMN1 , and 2 copy, 3 copy and 4 copy controls for SMN2 – were included along with a no template control. Data analysis was performed using QuantaSoft version 1.7.4.0917 (Bio-Rad) to determine the copy number variation (CNV) 10 , 11 (Fig. 1 ). SMN2 copy number was determined only for SMA-positive cases with a homozygous SMN1 exon 7 deletion to assess disease severity and prognosis. Results and Discussion SMA Patient Distribution and Diagnostic Yield in a multi-Arab population Between June 2019 and August 2023, 171 pediatric patients (51% females; mostly infants) (Fig. 2 A) presenting with hypotonia and/or muscle weakness were referred to Al Jalila Genomics Centre for diagnostic SMA testing. Patients, representing 18 countries, were mostly Arabs (82%) with the majority from Saudi Arabia (29%), UAE (25%) and Iraq (10%) (Fig. 2 B). Testing was positive in 58 cases, making up an overall diagnostic yield of 33.9% (Fig. 2 C), which varied by nationality (Fig. 2 B); yield was significantly higher among patients from Iraq (53%) relative to the UAE (19%) (P = 0.012; Fisher Exact Test). Determination of SMN2 copy number in SMA positive cases showed that the majority (71%) had 2 SMN2 copies, consistent with an earlier onset (Fig. 2 D) and a more likely severe phenotype (SMA type I) 7 , 12 . Average test turnaround time was 5 working days, with more than half (56%) receiving results in ≤ 4 working days (Fig. 2 E). SMA epidemiology in the United Arab Emirates We attempted to estimate the incidence of SMA in the UAE using the number of Emirati SMA patients born in a given year, as diagnosed by our laboratory during this period, divided by total annual live births in this population (which was 31,064 in 2021) 13 . However, since not all SMA diagnostic testing in the UAE is referred to our laboratory and due to the lack of national SMA registry, it is likely that this clinical-based incidence estimation to be inaccurate. To gain better insight into SMA epidemiology in the UAE, we genetically screened a total of 1,252 newborns (51% males, 49% females) recruited from 11 local maternity hospitals across the country (Fig. 3 A). Newborns aged ≤ 3 months and were generally healthy with no family history of SMA. Results from genetic screening revealed that 19 newborns (47% males, 53% females) were carriers for SMN1 deletion (Fig. 3 B), indicating a carrier frequency of 1 in 66 (1.5%) and an SMA allele frequency (q) of 0.0076 (Table 1 ). None of the newborns tested had a homozygous SMN1 deletion. Assuming Hardy–Weinberg equilibrium, disease burden or incidence (q 2 ) can be calculated as 1 in 17,368 individuals. However, considering the non-random mating in this population, a more appropriate estimate for incidence would be q x F 14 , where F represents the coefficient of inbreeding in the Emirati population (F = 0.0222) 15 , resulting in an incidence of 1 in 5,990 individuals (Table 1 ). It is important to note that this is likely an underestimate since 1) our testing method only detects deletions that account for 92% of cases, while 2) this method does not distinguish silent carriers, who possess two copies of the SMN1 gene on one allele (0 + 2), from normal noncarriers (1 + 1). SMA Epidemiology in other Arab populations Genetic newborn screening studies have been limited in most Arab countries. A study from Morocco reported a carrier frequency of 1 in 25 and a prevalence of 1:1900, though this was based on a small sample of 150 Moroccan newborns 16 . While this work was in preparation, a study was published whereby screening 4,189 normal Saudi volunteers determined a carrier frequency of 1 in 38 17 . Using this SMA allele frequency, and the coefficient of inbreeding in Saudi Arabia 18 , we estimated SMA incidence in this country to be 1 in 3,192 (Table 1 ), which is consistent with that estimated by authors in this study (32 in 100,000 or 1 in 3,125 births) 17 . Those estimates suggest the SMA carrier frequency and incidence in Saudi Arabia are both higher than those estimated in the UAE; findings which might be consistent with the observed higher SMA diagnostic trend in Saudi patients compared to those in the UAE (Fig. 2 B). Table 1 SMA genetic epidemiology in two Arab populations based on screening studies Country UAE* KSA 17 Sample Size (N) 1,252 4,198 Carrier Frequency = number of carriers divided by total number of participants (N) 1:66 (1.5%) 1:39 (2.6%) Allele Frequency (q) = number of carriers divided by total number of chromosomes (N x 2) 0.0076 0.0128 Coefficient of inbreeding (F) 0.0222 14 0.0241 14,18 Estimated incidence = q x F 1:5,990 1:3,192 *Data from this study; UAE, United Arab Emirates; KSA, Kingdom of Saudi Arabia The case for premarital genomic screening The tragic loss of a baby to SMA in Australia has fueled a large-scale reproductive carrier screening program for 750 genetic conditions (“Mackenzie’s Mission”) in Australia 19 . The estimated SMA incidence in both Arab countries studied here is significantly higher than that in other populations worldwide 7 , a finding which is consistent with the expectedly higher incidence of recessive disorders in Arab populations, suggesting that premarital genetic screening is likely to be an effective preventive measure in those populations. Based on the aforementioned estimate of SMA incidence in the UAE (Table 1 ) and the average annual Emirati birth rate, we conservatively anticipate that 5 births per year will be affected with SMA, necessitating gene therapy at a total cost of $ 10.5 million ( $ 2.1 million per patient; other long term treatment options, such as Spinraza, have a higher cost). However, if SMA premarital screening is implemented, the projected total cost of screening Emirati marriages would be $ 0.49 million annually (Table 2 ). Couples at risk will have the option for pre-implementation genetic testing (PGT) and in vitro fertilization (IVF) at a cost of up to $ 30,000 per couple 20 (Table 2 ). Similarly, average annual birth count among Saudi Nationals (18.8 million) is 511,000 21,22 . Therefore, it is expected that 160 births will be affected with SMA per year, requiring $ 336 million for treatment. However, the cost of SMA premarital screening for the annual 141,000 Saudi marriages in KSA 22 , would be around $ 7 million, along with a total cost of $ 4.8 million in PGT/IVF for at risk couples (Table 2 ). Table 2 Estimates of SMA births in UAE and KSA and the associated cost of postnatal treatment versus premarital screening United Arab Emirates Saudi Arabia Annual births 13 , 21 , 22 33,625 511,000 SMA livebirths per year * 5 160 Cost of gene therapy # $ 10.5 million $ 336 million Annual marriage rate 13 , 21 , 22 9,875 141,000 Cost of Premarital screening ^ $ 0.49 million $ 7 million Cost of PGT/IVF $ $ 150,000 $ 4.8 million Cost reduction & $ 9.86 million (16-fold) $ 324.2 million (28-fold) *Calculated by multiplying incidence in Table 1 by annual births in each country; # $2.1 million dollar; ^ Calculated by multiplying cost of SMA testing ($50) per couple; $ calculated by multiplying the number of couples expected to have an SMA birth and requiring PGT/IVF (pre-implementation genetic testing/ in vitro fertilization) by cost of PGT/IVF (30,000 USD 20 ); & calculated by subtracting cost of premarital screening and PGT/IVF from total cost of gene therapy We estimate the disease burden or incidence of SMA in the UAE. Using data from the UAE (this study) and Saudi Arabia 17 , we demonstrate that, in addition to potentially preventing new SMA cases, premarital screening and subsequent PGT/IVF for at-risk couples, can be a highly cost-effective measure from a public health standpoint, leading to an expected 16 to 28-fold cost reduction compared to postnatal disease treatment. Interestingly, the cost savings due to premarital screening for this one disease (~ $ 10 million in UAE and $ 324 million in KSA) is sufficient to fund more comprehensive premarital genomic screening programs encompassing hundreds of recessive disorders in both countries. We strongly advocate for the implementation of comprehensive genomic premarital screening in Arab populations with similarly high consanguinity rates. Declarations Competing Interests Authors declare no competing interests. Author Contributions AAT conceived study and obtained funding. MK, NA, KA, ME, SD, YS, AA, SA, KF, JS, and SA recruited and consented families for SMA genetic screening. FR, ME, IC and AAT performed all analysis. AAT and AAK obtained ethical approvals. FA, TL and AAA helped with epidemiological analysis. FR and AAT wrote first manuscript draft. Acknowledgements The spinal muscular atrophy pilot study is being supported by an unrestricted medical grant from Novartis/AveXis. References Lunn M, Wang C. Spinal muscular atrophy. The Lancet . 371 (9630):2120-2133 (2008). D'Amico, A., Mercuri, E., Tiziano, F.D. et al. Spinal muscular atrophy. Orphanet J Rare Dis . 6 , 71 (2011). Farrar M, Kiernan M. The Genetics of Spinal Muscular Atrophy: Progress and Challenges. Neurotherapeutics . 12 (2), 290-302 (2014). Keinath M, Prior D, Prior T. Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance. The Application of Clinical Genetics . 14 :11-25 (2021). Gene - NCBI [Internet]. Ncbi.nlm.nih.gov. [cited 7 Sept 2023]. 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The Australian Reproductive Genetic Carrier Screening Project (Mackenzie’s Mission): Design and Implementation. J Pers Med . 12 (11):1781 (2022). Antero, M. F. et al. Cost-effectiveness of preimplementation genetic testing for aneuploidy for fresh donor oocyte cycles. F S Rep . 2 (1):36-42 (2021). Saudi Census. Accessed December 14, 2023. https://portal.saudicensus.sa/portal/public/1/15/45?type=DASHBOARD GCC-STAT. Accessed December 14, 2023. https://dp.gccstat.org/en/DataAnalysis Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Published Journal Publication published 15 Jun, 2024 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Centre","correspondingAuthor":false,"prefix":"","firstName":"Fowzan","middleName":"","lastName":"Alkuraya","suffix":""},{"id":267150462,"identity":"1e8a008b-9f8e-4641-9b32-78108824e74c","order_by":16,"name":"Tom Loney","email":"","orcid":"https://orcid.org/0000-0003-1687-6587","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Tom","middleName":"","lastName":"Loney","suffix":""},{"id":267150463,"identity":"3eac301e-e4e2-40a6-a3b0-93acaae58c0e","order_by":17,"name":"Alawi Alsheikh-Ali","email":"","orcid":"","institution":"Mohammed Bin Rashid University of Medicine and Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Alawi","middleName":"","lastName":"Alsheikh-Ali","suffix":""},{"id":267150464,"identity":"b43fc222-14fd-4e02-95c5-4fe705b636d1","order_by":18,"name":"Abdulla Al Khayat","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Abdulla","middleName":"Al","lastName":"Khayat","suffix":""}],"badges":[],"createdAt":"2024-01-13 14:40:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3860416/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3860416/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s43856-024-00548-1","type":"published","date":"2024-06-15T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49714146,"identity":"063fbb26-7c5c-4ae4-8fbf-3a17bfac4e79","added_by":"auto","created_at":"2024-01-16 20:45:51","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":220784,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDroplet Digital PCR workflow for SMN1 and SMN2 copy number analysis\u003c/strong\u003e. Probes specific to either \u003cem\u003eSMN1\u003c/em\u003e or \u003cem\u003eSMN2\u003c/em\u003e (Target, blue) or a reference gene (\u003cem\u003eRPP30\u003c/em\u003e, green) were used. The number of target droplets (blue) were compared to that of reference droplets (green) to assess the copy number status of \u003cem\u003eSMN1\u003c/em\u003e or \u003cem\u003eSMN2 \u003c/em\u003e(as illustrated).\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3860416/v1/818c4a5792780561c4b6e75e.jpg"},{"id":49714147,"identity":"2eb5c983-dd9f-48df-a8f9-0f7ecc38c483","added_by":"auto","created_at":"2024-01-16 20:45:51","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":457510,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSMA patients’ demographics. (A) \u003c/strong\u003eDistribution of patients by age and gender.\u003cstrong\u003e (B) \u003c/strong\u003eDistribution of patients (n=171) and diagnostic yield by nationality. \u003cstrong\u003e(C) \u003c/strong\u003eOverall diagnostic yield. \u003cstrong\u003e(D)\u003c/strong\u003e \u003cem\u003eSMN2\u003c/em\u003e copy number status in SMA patients of different ages. \u003cstrong\u003e(E)\u003c/strong\u003e Testing turnaround time.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3860416/v1/9a0916a69579919166acf402.jpg"},{"id":49714148,"identity":"eb4c268b-7736-4a5f-9f67-0e41c05fef26","added_by":"auto","created_at":"2024-01-16 20:45:51","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":410368,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eRecruiting sites for SMA genetic screening throughout the UAE. \u003cstrong\u003e(B)\u003c/strong\u003e Distribution of SMN1 copy number in Emirati newborns (N = 1,252).\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3860416/v1/f931f214cb1351e6208b4afd.jpg"},{"id":58435208,"identity":"ef30b900-2f1f-47cc-8e7f-b4b3a0955329","added_by":"auto","created_at":"2024-06-16 07:06:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1654069,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3860416/v1/935606f1-a87d-4a9a-9ecd-d45ace121e21.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Spinal muscular atrophy genetic epidemiology and the case for premarital genomic screening in Arab populations","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSpinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder characterized by irreversible loss of alpha motor neurons in the spinal cord and lower brainstem resulting in progressive muscle atrophy and weakness\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Its clinical manifestation is highly variable, ranging in onset from intrauterine to adulthood, and in severity from minor muscle weakness to severe paralysis and death. Accordingly, SMA has been classified into four primary subtypes: type I, type II, type III and type IV. Type I, known as infantile SMA, is the most common and severe form of the disease, seen in ~\u0026thinsp;50%\u003csup\u003e2\u003c/sup\u003e of affected patients and has an onset before 6 months of age. If untreated, death generally occurs within the first two years of life due to respiratory failure\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSMA is an autosomal recessive disorder caused by biallelic pathogenic variants in the telomeric survival motor neuron 1 (\u003cem\u003eSMN1\u003c/em\u003e) gene located on chromosome 5q13\u003csup\u003e5\u003c/sup\u003e. Most affected patients (92%) harbor a homozygous deletion of \u003cem\u003eSMN1\u003c/em\u003e exon 7, while a small subset (4%) are compound heterozygotes for exon 7 deletion on one allele coupled with a small intragenic variant on the other allele\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. In rare occasions (4%), SMA can be due to over 30 genes identified, other than \u003cem\u003eSMN1\u003c/em\u003e\u003csup\u003e3,6,7\u003c/sup\u003e. Though an almost identical homologue to \u003cem\u003eSMN1\u003c/em\u003e, \u003cem\u003eSMN2\u003c/em\u003e can only partially compensate for \u003cem\u003eSMN1\u003c/em\u003e loss. Increase in \u003cem\u003eSMN2\u003c/em\u003e copy number has been associated with milder forms of SMA and, therefore, has prognostic value. Of patients with 4 copies of \u003cem\u003eSMN2\u003c/em\u003e, 1% of patients had SMA type I, 11% had SMA type II and 88% had SMA type III or type IV\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSMA is globally the second most common fatal autosomal recessive disorder. Based on available data in populations of European ancestry, SMA highest incidence and carrier frequency are around 1 in 8000 and 1 in 45, respectively\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. These figures are expected to be even higher in regions with high rates of consanguinity, particularly in the Middle East where the incidence has been predicted to range between 10 to 193 in 100,000 live births, almost 40-fold higher than in Western populations\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. However, there is a lack of data to accurately estimate SMA epidemiology across Arab populations. As such, the primary aim of this study was to estimate the carrier frequency and incidence of SMA in the United Arab Emirates (UAE), and to investigate efficient approaches for disease prevention.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Participants\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003eClinical Patient Cohort\u003c/h2\u003e \u003cp\u003ePediatric patients (age\u0026thinsp;\u0026lt;\u0026thinsp;18 years old) were referred for diagnostic SMA testing at the Genomics Centre in Al Jalila Childrens\u0026rsquo; Specialty Hospital between June 2019 and August 2023. Al Jalila Children\u0026rsquo;s is the only tertiary pediatric center in the UAE and is the main referral center for pediatric patients with rare diseases across the UAE. Peripheral blood samples were obtained from patients suspected with SMA and clinical data was provided by the referring physician either through the electronic medical record, for internal patients, or on requisition forms, for external patients. The de-identified, reporting of clinical cohort in this study was approved by the Dubai Healthcare Authority Research Ethics Committee (DSREC-07/203_06), which determined that this study meets the exemption criteria with a waiver of informed consent. A subset of this clinical cohort was previously published\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, though in addition to increasing cohort size, this current study includes additional information on age ranges, diagnostic yield stratified by nationality, and \u003cem\u003eSMN2\u003c/em\u003e copy number status.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSMA genetic screening initiative in Emirati Newborn\u003c/h2\u003e \u003cp\u003eA network of eleven local maternity hospitals across the UAE was established to conduct the country\u0026rsquo;s first large scale representative genetic newborn screening study for SMA. Recruitment and consenting of Emirati newborns\u0026rsquo; (age\u0026thinsp;\u0026le;\u0026thinsp;3 months) families were carried out by neonatologists/pediatricians at each hospital. Peripheral blood samples were obtained from each participant and clinical data were provided by the recruiting physician through an electronic collection data sheet. Samples were transported to Al Jalila Genomics Centre where SMA testing was performed. The study was approved by the Dubai Health Authority Scientific Research Ethics Committee (DSREC-06/2021_20), Ministry of Health and Prevention Research Ethics Committee (MOHAP/DXB-REC/SOO/No.81/2021) and Abu Dhabi Health Research and Technology Ethics Committee (DOH/CVDC/2022/1626).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eDNA Extraction\u003c/h2\u003e \u003cp\u003eGenomic DNA was extracted from peripheral whole blood using the QIAsymphony DSP DNA Kit (Qiagen, Hilden, Germany) and QIAsymphony automated nucleic acid extraction instrument, according to the manufacturer's instructions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSMA Copy Number Analysis\u003c/h2\u003e \u003cp\u003e \u003cem\u003eSMN1\u003c/em\u003e and \u003cem\u003eSMN2\u003c/em\u003e copy numbers were determined by Digital droplet PCR (ddPCR) technology using predesigned proprietary ddPCR assay kits for \u003cem\u003eSMN1\u003c/em\u003e (Catalog No: 186\u0026ndash;3500, Bio-Rad) and \u003cem\u003eSMN2\u003c/em\u003e (Catalog No: 186\u0026ndash;3503, Bio-Rad). The predesigned Bio-Rad assays include reagents to detect both the target gene (\u003cem\u003eSMN1\u003c/em\u003e or \u003cem\u003eSMN2\u003c/em\u003e) and an internal reference gene (\u003cem\u003eRPP30\u003c/em\u003e). In addition, experimental controls \u0026ndash; 0 copy, 1 copy and 2 copy controls for \u003cem\u003eSMN1\u003c/em\u003e, and 2 copy, 3 copy and 4 copy controls for \u003cem\u003eSMN2\u003c/em\u003e \u0026ndash; were included along with a no template control.\u003c/p\u003e \u003cp\u003eData analysis was performed using QuantaSoft version 1.7.4.0917 (Bio-Rad) to determine the copy number variation (CNV)\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). \u003cem\u003eSMN2\u003c/em\u003e copy number was determined only for SMA-positive cases with a homozygous \u003cem\u003eSMN1\u003c/em\u003e exon 7 deletion to assess disease severity and prognosis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Results and Discussion","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSMA Patient Distribution and Diagnostic Yield in a multi-Arab population\u003c/h2\u003e \u003cp\u003eBetween June 2019 and August 2023, 171 pediatric patients (51% females; mostly infants) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA) presenting with hypotonia and/or muscle weakness were referred to Al Jalila Genomics Centre for diagnostic SMA testing. Patients, representing 18 countries, were mostly Arabs (82%) with the majority from Saudi Arabia (29%), UAE (25%) and Iraq (10%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003eTesting was positive in 58 cases, making up an overall diagnostic yield of 33.9% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC), which varied by nationality (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB); yield was significantly higher among patients from Iraq (53%) relative to the UAE (19%) (P\u0026thinsp;=\u0026thinsp;0.012; Fisher Exact Test). Determination of \u003cem\u003eSMN2\u003c/em\u003e copy number in SMA positive cases showed that the majority (71%) had 2 \u003cem\u003eSMN2\u003c/em\u003e copies, consistent with an earlier onset (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD) and a more likely severe phenotype (SMA type I)\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Average test turnaround time was 5 working days, with more than half (56%) receiving results in \u0026le;\u0026thinsp;4 working days (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSMA epidemiology in the United Arab Emirates\u003c/h2\u003e \u003cp\u003eWe attempted to estimate the incidence of SMA in the UAE using the number of Emirati SMA patients born in a given year, as diagnosed by our laboratory during this period, divided by total annual live births in this population (which was 31,064 in 2021)\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. However, since not all SMA diagnostic testing in the UAE is referred to our laboratory and due to the lack of national SMA registry, it is likely that this clinical-based incidence estimation to be inaccurate.\u003c/p\u003e \u003cp\u003eTo gain better insight into SMA epidemiology in the UAE, we genetically screened a total of 1,252 newborns (51% males, 49% females) recruited from 11 local maternity hospitals across the country (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Newborns aged\u0026thinsp;\u0026le;\u0026thinsp;3 months and were generally healthy with no family history of SMA. Results from genetic screening revealed that 19 newborns (47% males, 53% females) were carriers for \u003cem\u003eSMN1\u003c/em\u003e deletion (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB), indicating a carrier frequency of 1 in 66 (1.5%) and an SMA allele frequency (q) of 0.0076 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). None of the newborns tested had a homozygous \u003cem\u003eSMN1\u003c/em\u003e deletion.\u003c/p\u003e\u003cp\u003eAssuming Hardy\u0026ndash;Weinberg equilibrium, disease burden or incidence (q\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e) can be calculated as 1 in 17,368 individuals. However, considering the non-random mating in this population, a more appropriate estimate for incidence would be q x F\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, where F represents the coefficient of inbreeding in the Emirati population (F\u0026thinsp;=\u0026thinsp;0.0222)\u003csup\u003e15\u003c/sup\u003e, resulting in an incidence of 1 in 5,990 individuals (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt is important to note that this is likely an underestimate since 1) our testing method only detects deletions that account for 92% of cases, while 2) this method does not distinguish silent carriers, who possess two copies of the \u003cem\u003eSMN1\u003c/em\u003e gene on one allele (0\u0026thinsp;+\u0026thinsp;2), from normal noncarriers (1\u0026thinsp;+\u0026thinsp;1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSMA Epidemiology in other Arab populations\u003c/h2\u003e \u003cp\u003eGenetic newborn screening studies have been limited in most Arab countries. A study from Morocco reported a carrier frequency of 1 in 25 and a prevalence of 1:1900, though this was based on a small sample of 150 Moroccan newborns\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. While this work was in preparation, a study was published whereby screening 4,189 normal Saudi volunteers determined a carrier frequency of 1 in 38\u003csup\u003e17\u003c/sup\u003e. Using this SMA allele frequency, and the coefficient of inbreeding in Saudi Arabia\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, we estimated SMA incidence in this country to be 1 in 3,192 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), which is consistent with that estimated by authors in this study (32 in 100,000 or 1 in 3,125 births)\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Those estimates suggest the SMA carrier frequency and incidence in Saudi Arabia are both higher than those estimated in the UAE; findings which might be consistent with the observed higher SMA diagnostic trend in Saudi patients compared to those in the UAE (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\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\u003eSMA genetic epidemiology in two Arab populations based on screening studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUAE*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eKSA\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\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\u003e\u003cb\u003eSample Size (N)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,252\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4,198\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCarrier Frequency\u0026thinsp;=\u003c/b\u003e\u0026thinsp;number of carriers divided by total number of participants (N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1:66 (1.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1:39 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAllele Frequency (q)\u0026thinsp;=\u003c/b\u003e\u0026thinsp;number of carriers divided by total number of chromosomes (N x 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.0076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.0128\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCoefficient of inbreeding (F)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.0222\u003csup\u003e14\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.0241\u003csup\u003e14,18\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEstimated incidence\u0026thinsp;=\u0026thinsp;q x F\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1:5,990\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1:3,192\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e*Data from this study; UAE, United Arab Emirates; KSA, Kingdom of Saudi Arabia\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eThe case for premarital genomic screening\u003c/h2\u003e \u003cp\u003eThe tragic loss of a baby to SMA in Australia has fueled a large-scale reproductive carrier screening program for 750 genetic conditions (\u0026ldquo;Mackenzie\u0026rsquo;s Mission\u0026rdquo;) in Australia\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. The estimated SMA incidence in both Arab countries studied here is significantly higher than that in other populations worldwide\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, a finding which is consistent with the expectedly higher incidence of recessive disorders in Arab populations, suggesting that premarital genetic screening is likely to be an effective preventive measure in those populations.\u003c/p\u003e \u003cp\u003eBased on the aforementioned estimate of SMA incidence in the UAE (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and the average annual Emirati birth rate, we conservatively anticipate that 5 births per year will be affected with SMA, necessitating gene therapy at a total cost of \u003cspan\u003e$\u003c/span\u003e10.5\u0026nbsp;million (\u003cspan\u003e$\u003c/span\u003e2.1\u0026nbsp;million per patient; other long term treatment options, such as Spinraza, have a higher cost). However, if SMA premarital screening is implemented, the projected total cost of screening Emirati marriages would be \u003cspan\u003e$\u003c/span\u003e0.49\u0026nbsp;million annually (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Couples at risk will have the option for pre-implementation genetic testing (PGT) and \u003cem\u003ein vitro\u003c/em\u003e fertilization (IVF) at a cost of up to \u003cspan\u003e$\u003c/span\u003e30,000 per couple\u003csup\u003e \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e \u003c/sup\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSimilarly, average annual birth count among Saudi Nationals (18.8\u0026nbsp;million) is 511,000\u003csup\u003e21,22\u003c/sup\u003e. Therefore, it is expected that 160 births will be affected with SMA per year, requiring \u003cspan\u003e$\u003c/span\u003e336\u0026nbsp;million for treatment. However, the cost of SMA premarital screening for the annual 141,000 Saudi marriages in KSA\u003csup\u003e \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e \u003c/sup\u003e, would be around \u003cspan\u003e$\u003c/span\u003e7\u0026nbsp;million, along with a total cost of \u003cspan\u003e$\u003c/span\u003e4.8\u0026nbsp;million in PGT/IVF for at risk couples (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\u003eEstimates of SMA births in UAE and KSA and the associated cost of postnatal treatment versus premarital screening\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnited Arab Emirates\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSaudi Arabia\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnnual births\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33,625\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e511,000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSMA livebirths per year\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e160\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCost of gene therapy\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan\u003e$\u003c/span\u003e10.5 million\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cspan\u003e$\u003c/span\u003e336 million\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnnual marriage rate\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,875\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e141,000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCost of Premarital screening\u003csup\u003e^\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan\u003e$\u003c/span\u003e0.49 million\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cspan\u003e$\u003c/span\u003e7 million\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCost of PGT/IVF\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan\u003e$\u003c/span\u003e150,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cspan\u003e$\u003c/span\u003e4.8 million\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCost reduction\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan\u003e$\u003c/span\u003e9.86\u0026nbsp;million (16-fold)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cspan\u003e$\u003c/span\u003e324.2\u0026nbsp;million (28-fold)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e*Calculated by multiplying incidence in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e by annual births in each country; \u003csup\u003e#\u003c/sup\u003e$2.1\u0026nbsp;million dollar; \u003csup\u003e^\u003c/sup\u003eCalculated by multiplying cost of SMA testing ($50) per couple; \u003csup\u003e$\u003c/sup\u003ecalculated by multiplying the number of couples expected to have an SMA birth and requiring PGT/IVF (pre-implementation genetic testing/\u003cem\u003ein vitro\u003c/em\u003e fertilization) by cost of PGT/IVF (30,000 USD\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e); \u003csup\u003e\u0026amp;\u003c/sup\u003ecalculated by subtracting cost of premarital screening and PGT/IVF from total cost of gene therapy\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe estimate the disease burden or incidence of SMA in the UAE. Using data from the UAE (this study) and Saudi Arabia\u003csup\u003e \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e \u003c/sup\u003e, we demonstrate that, in addition to potentially preventing new SMA cases, premarital screening and subsequent PGT/IVF for at-risk couples, can be a highly cost-effective measure from a public health standpoint, leading to an expected 16 to 28-fold cost reduction compared to postnatal disease treatment. Interestingly, the cost savings due to premarital screening for this one disease (~\u003cspan\u003e$\u003c/span\u003e10\u0026nbsp;million in UAE and \u003cspan\u003e$\u003c/span\u003e324\u0026nbsp;million in KSA) is sufficient to fund more comprehensive premarital genomic screening programs encompassing hundreds of recessive disorders in both countries. We strongly advocate for the implementation of comprehensive genomic premarital screening in Arab populations with similarly high consanguinity rates.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting Interests\u003c/h2\u003e \u003cp\u003eAuthors declare no competing interests.\u003c/p\u003e \u003ch2\u003eAuthor Contributions\u003c/h2\u003e \u003cp\u003eAAT conceived study and obtained funding. MK, NA, KA, ME, SD, YS, AA, SA, KF, JS, and SA recruited and consented families for SMA genetic screening. FR, ME, IC and AAT performed all analysis. AAT and AAK obtained ethical approvals. FA, TL and AAA helped with epidemiological analysis. FR and AAT wrote first manuscript draft.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThe spinal muscular atrophy pilot study is being supported by an unrestricted medical grant from Novartis/AveXis.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLunn M, Wang C. Spinal muscular atrophy. \u003cem\u003eThe Lancet\u003c/em\u003e. \u003cstrong\u003e371\u003c/strong\u003e(9630):2120-2133 (2008).\u003c/li\u003e\n\u003cli\u003eD\u0026apos;Amico, A., Mercuri, E., Tiziano, F.D. et al. Spinal muscular atrophy. \u003cem\u003eOrphanet J Rare Dis\u003c/em\u003e. \u003cstrong\u003e6\u003c/strong\u003e, 71 (2011).\u003c/li\u003e\n\u003cli\u003eFarrar M, Kiernan M. The Genetics of Spinal Muscular Atrophy: Progress and Challenges. \u003cem\u003eNeurotherapeutics\u003c/em\u003e.\u003cstrong\u003e12\u003c/strong\u003e(2), 290-302 (2014).\u003c/li\u003e\n\u003cli\u003eKeinath M, Prior D, Prior T. 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The Australian Reproductive Genetic Carrier Screening Project (Mackenzie\u0026rsquo;s Mission): Design and Implementation. \u003cem\u003eJ Pers Med\u003c/em\u003e. \u003cstrong\u003e12\u003c/strong\u003e(11):1781 (2022).\u003c/li\u003e\n\u003cli\u003eAntero, M. F. et al. Cost-effectiveness of preimplementation genetic testing for aneuploidy for fresh donor oocyte cycles. \u003cem\u003eF S Rep\u003c/em\u003e. \u003cstrong\u003e2\u003c/strong\u003e(1):36-42 (2021).\u003c/li\u003e\n\u003cli\u003eSaudi Census. Accessed December 14, 2023. https://portal.saudicensus.sa/portal/public/1/15/45?type=DASHBOARD\u003c/li\u003e\n\u003cli\u003eGCC-STAT. Accessed December 14, 2023. https://dp.gccstat.org/en/DataAnalysis\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3860416/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3860416/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSpinal muscular atrophy (SMA) is a fatal autosomal recessive disorder for which several treatment options, including gene therapy, have become available. SMA incidence has not been well-characterized in most Arab countries where rates of consanguinity are high. Understanding SMA disease epidemiology has significant implications for screening, prevention, and treatment in those populations.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe preformed SMA diagnostic testing in a clinical multi-national patient cohort (N\u0026thinsp;=\u0026thinsp;171) referred for hypotonia and/or muscle weakness. In addition, we carried out genetic newborn screening for SMA on 1,252 healthy Emirati newborns to estimate the carrier frequency and incidence of the disease in the United Arab Emirates.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePatients referred for SMA genetic testing were mostly Arabs (82%) representing 18 countries. The overall diagnostic yield was 33.9%, which was higher (\u0026gt;\u0026thinsp;50%) for certain nationalities. Most patients (71%) had two \u003cem\u003eSMN2\u003c/em\u003e copies and earlier disease onset. For the first time, we estimate SMA carrier frequency (1.5%) and incidence of the disease (1 in 5,990 live births) in the United Arab Emirates. Using birth and marriage rates in two Arab populations (United Arab Emirates and Saudi Arabia), as well as disease incidence in both countries, we show that, besides preventing new cases, premarital genetic screening could potentially lead to \u003cspan\u003e$\u003c/span\u003e10 to \u003cspan\u003e$\u003c/span\u003e324\u0026nbsp;million, respectively, annual cost savings relative to postnatal treatment.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe SMA carrier frequency and incidence we document suggests high potential benefit for universal implementation of premarital genomic screening for a wide range of recessive disorders in Arab populations.\u003c/p\u003e","manuscriptTitle":"Spinal muscular atrophy genetic epidemiology and the case for premarital genomic screening in Arab populations","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-16 20:45:46","doi":"10.21203/rs.3.rs-3860416/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0acf9789-3d62-4a0e-8b78-75920694c9ef","owner":[],"postedDate":"January 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":28140952,"name":"Health sciences/Health care/Disease prevention/Preventive medicine"},{"id":28140953,"name":"Biological sciences/Genetics/Population genetics/Genetic variation"}],"tags":[],"updatedAt":"2024-06-16T07:06:30+00:00","versionOfRecord":{"articleIdentity":"rs-3860416","link":"https://doi.org/10.1038/s43856-024-00548-1","journal":{"identity":"communications-medicine","isVorOnly":false,"title":"Communications Medicine"},"publishedOn":"2024-06-15 04:00:00","publishedOnDateReadable":"June 15th, 2024"},"versionCreatedAt":"2024-01-16 20:45:46","video":"","vorDoi":"10.1038/s43856-024-00548-1","vorDoiUrl":"https://doi.org/10.1038/s43856-024-00548-1","workflowStages":[]},"version":"v1","identity":"rs-3860416","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3860416","identity":"rs-3860416","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}