Genetic and Clinical Landscape of Duchenne Muscular Dystrophy in Guatemala: Insights from a National Study

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Despite its well-documented genetic basis, no previous studies have characterised DMD in Guatemala. We analysed 33 genetically confirmed cases to estimate prevalence, describe the mutation spectrum, and assess clinical features. Prevalence was 0.61 per 100,000 men under 30. Symptoms began before age 5 in 85% of cases, yet 60% were diagnosed after age 6, highlighting significant diagnostic delays. Deletions were the most common mutation (55%), followed by point mutations (30%) and duplications (15%), with two novel variants identified. Most deletions clustered in the exon 45–55 hotspot. Nearly half of the cases were eligible for exon-skipping therapies. These findings reveal genetic heterogeneity in the Guatemalan population, substantial delays in diagnosis, and the need for improved access to genetic testing, targeted treatments, and a national DMD registry. Biological sciences/Genetics Health sciences/Diseases Health sciences/Medical research Introduction Duchenne Muscular Dystrophy is a severe, progressive, and disabling neuromuscular disease, one of the most common muscular dystrophies. 1 It is considered an inherited, recessive, X-linked (Xp21) myopathy caused by mutations in the DMD gene. 2 The reported worldwide incidence is 1:3 per 600-9,300 live births. 3 The worldwide prevalence has been estimated at 3.6 per 100,000 population but varies by geographic area. 4 Countries with a high Economic Development Index (HEDI) tend to have more robust epidemiological data, reflecting better access to diagnostic technologies and disease surveillance systems. In contrast, countries with medium or low EDI often lack such data, highlighting significant limitaions. Nowhere is this more evident than in Guatemala, where no prevalence data for Duchenne muscular dystrophy is available. By comparison, Chile, a country with more developed healthcare infrastructure, reports a prevalence of 11.51 per 100,000 men under 30 years, illustrating the regional variation in both disease burden and the ability to measure it, illustrating the regional variation in both disease burden and detection capacity 5 6 . Another reported and related factor is the economic burden of this disease as it progresses to the critical stages of the disease, with the cost of the disease increasing by up to 16 times. 3 The molecular basis of DMD is complex, over 7,000 variants in the DMD gene are thought to be associated with Duchenne Muscular Dystrophy, with deletions and duplications of exons being the most frequent variants at 80% and 20% with point gene variants. 7 The DMD gene is 2.4 Mb in size and harbors 79 exons. This gene produces the protein Dystrophin which is part of the dystrophin-associated protein complex with a structural function in helping to stabilize the sarcolemma and protecting muscle fibers from damage and necrosis caused by prolonged contraction. When reduced but functional dystrophin is present it is considered Becker Muscular Dystrophy (BMD-OMIM #300376) which carries a better prognosis for the patient. 8 The structural and functional variations of dystrophin depend on the type of mutation in the DMD gene, which can range from an affected but functional protein to a non-functional or even absent protein. As a result, they can lead to different forms and severities of the disease. Identifying the mutational spectrum of the DMD gene is important to guide and apply feasible therapies that are mutation-specific. There is a lack of knowledge about the mutation profile in Guatemalan patients. Identifying the spectrum in the Guatemalan population is necessary to determine if they are eligible for treatment. 9 , 10 , 11 Currently, Guatemala lacks an epidemiological surveillance system for neuromuscular and rare diseases and the genetic profile of patients affected by DMD is unknown. Many cases, especially in rural areas, are under-diagnosed. This article aims to present the national urban-rural results of an epidemiological, socio-demographic, clinical characteristics, and mutational spectrum in the Guatemalan population. Understanding the genetic diversity of Duchenne muscular dystrophy is crucial for several reasons. It provides insights into genetic risk factors, offering valuable knowledge about previously unknown aspects of the disorder. Moreover, studying DMD in diverse populations helps to develop more inclusive and precise genetic tests, diagnostics, and therapies. Without expanding genetic research beyond Western populations, there is a significant risk of overlooking variants critical to understanding DMD in other ethnic and regional groups. Currently, there is limited knowledge of the genetic profile of DMD in Guatemala and other Central American populations. Most genetic studies of DMD focus on regions with robust healthcare infrastructure, leaving gaps in our understanding of how the disease manifests in lower-resource settings. This study seeks to address these gaps by characterising the genetic and clinical features of DMD in Guatemala, a population with a distinct socio-economic and genetic background. By analysing the prevalence, mutational spectrum, and clinical presentation of DMD in this region, we aim to identify novel genetic variants and assess whether previously known mutations are similarly implicated. Understanding these region-specific genetic factors could provide new insights into the disease mechanism and support the development of targeted therapies and diagnostic tools, contributing to a more comprehensive global understanding of DMD. Methods Data collection During 16 months (October 2022 to January 2024), 33 (100%) active cases of any age, with clinical suspicion of DMD were detected from two national reference hospitals (73%) most important in the country, from the Social Security hospital (9%), Foundation for the Welfare of the Disabled (FUNDABIEM) (15%) and private clinic (3%). Patients with clinical suspicion of DMD, but with negative molecular test were excluded. A follow-up, cross-sectional, non-probability, convenience-based, analytical study was performed. For variant detection, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed by probe denaturation, ligation, Polymerase Chain Reaction (PCR) amplification, and fragment separation by capillary electrophoresis, using MRC Holland probes P034 and P035 that analyze all exons (79 exons), for deletions or duplications of the DMD gene. In cases where MLPA did not detect any deletions or duplications, sequencing of the gene was performed. Coffalyser.net software was used for bioinformatics analysis of the data obtained. 12 For DNA sequencing analysis, the DNB-SEQ400 next-generation mass sequencer was used. 13 The analysis was aimed at identifying variants included in exonic regions or splice regions, insertions, and small deletions. Genetic testing was performed by the GenCell Genética Avanzada laboratory in Bogotá, Colombia as well as the logistics of transporting blood (79%) and saliva (21%) samples. Data management and analysis A data collection form was developed that included demographic, social, economic, clinical, electrodiagnostic, and molecular laboratory studies. All data was recorded and re-recorded for recording errors or inconsistencies. This was carried out in the statistical program EPINFO V6.0 . 14 and descriptive statistics were obtained, with a confidence interval of 95%. The analysis and interpretation of genetic variants were performed using the open-access, web-based tool "DMD Open-access Variant Explore (DOVE)" 15 providing information on amino acid change, functional predictions at the protein level, length of the mutated sequence, and molecular eligibility for treatment based on specific variants to correct the reading frame. Whole-genome sequencing DNA was isolated from venous blood using standard methods. DNA concentration was set at 100ng/ul as measured by fluorimeter. DNA integrity was assessed using gel electrophoresis. All samples were sequenced using Illumina’s FastTrack services (San Diego, CA, USA) on the Illumina HiSeq 2000 (100bp paired-end reads) and HiSeqX platforms (150bp paired end reads), using PCR-free library preparations. Binary sequence alignment/map formats (BAM) were generated for each individual. The Project MinE genomes were aligned with Isaac (Illumina) to hg19. Quality Control Sample mismatch was tested using sex checks, where genetic sex was compared to reported gender. After quality control, the full set of gVCFs were merged together by first converting the gVCFs to Plink format and then merging all files together. This generated a single dataset containing all variant sites across all individuals. Non-autosomal chromosome and multi-allelic variants were excluded from pilot analyses. Results Thirty-seven (37) cases with clinically suspected Duchenne muscular dystrophy were detected and referred from different health institutions participating in the study. Four cases had negative genetic test results and were therefore excluded. This left 33 genetically confirmed cases with Duchenne muscular dystrophy that are part of this analysis. Again, it is confirmed that all genetically positive cases were male as DMD is an X-linked disease. The prevalence found for this study cohort was 0.61 per 100,000 men under 30 years (33/5.395,769 denominator according to projections based on the last census of Guatemala 2018). 16 Seventy-six percent of the cases detected for the first time were between six and ten years old, 48% were late school leavers, 55% were of middle socio-economic status, 15% were of kinship and 61% were from rural areas. Eighty-five percent of the cases started their symptomatology before the age of 5 years, but unfortunately, 60% of the cases were diagnosed after the age of 6 years. Table 1 presents the details of the molecular variants of the 33 cases detected. 23 (70%) cases presented deletion and duplication detected by MLPA, with deletions of one or more exons (55%) being the most frequent pathogenic variant detected, most of them (72%) found in one of the hot spots from exons 45 to 55. Six cases had deletions of a single exon, four of which were exon 45, one case of exon 50, and one case of exon 30, which was the only one found within the in-frame. Table 1 Spectrum of mutations found in patients with DMD in Guatemala No. Deleted exon 1 Exon duplicated 2 Exon with variant type 3 Variant type 4 DNA level change 5 Amino acid change 6 Length of mutated sequence 7 Potential Therapy 8 1 45–50 Frameshift p.Glu2147Leu*9 Exon 51 skip 2 2 Frameshift c.32 − 2_93+?dup p.Phe32Metfs*15 62 3 46–55 Frameshift c.6615-?_8217+?del p.Leu2206Thrfs*24 1603 Exon 45 skip 4 30 Frameshift c.4099dup p.Gln1367ProfsTer10 1 5 3 Frameshift c.6986dup p.Leu2330AlafsTer10 1 6 40 Frameshift c.5704_5707del p.Ser1902TyfsTer10 4 7 8–16 Frameshift c.650-?_1992+?dup p. ? 8 3–7 Frameshift c.94-?_649+?del p.Phe32Metfs*13 556 Exon 8 skip 9 45 Frameshift c.6439-?_8390+?del p.Glu2147Alafs*17 176 Exon 44 skip 10 45–56 Frameshift p.Glu2147Valfs*8 1952 Exon 44 skip 11 45 Frameshift c.6439-?_8390+?del p.Glu2147Alafs*17 176 Exon 44 skip 12 40 Nonsense c.5641C > T p.Gln1881Ter 1 Ataluren 13 49–50 Frameshift c.7099-?_7309 + del p.Glu2367Leufs*9 211 Exon 51 skip 14 5 Nonsense c.354G > A p.Trp118Ter 1 Ataluren 15 5 Nonsense c.354G > A p.Trp118Ter 1 Ataluren 16 45 Frameshift c.6439-?_8390+?del p.Glu2147Alafs*17 176 17 8–12 Frameshift p. ? 18 5 Nonsense c.354G > A p.Trp118Ter 1 Ataluren 19 46–51 Frameshift p.Leu2206Glnfs*23 928 Exon 45 skip 20 2–7 Frameshift 21 46–50 Frameshift c.6615-?_7309 + del p.Arg2205Serfs*16 695 Exon 51 skip 22 5–7 Frameshift c.265-?_649+?del p.Val89Metfs*13 385 Exon 8 skip 23 10–11 Frameshift c.961-?_1331+?del p.His321Phefs*3 371 Exon 12 skip 24 45 Frameshift c.6439-?_8390+?del p.Glu2147Alafs*17 176 Exon 44 skip 25 ? Nonsense c.7683G > A p.Trp2561Ter 1 Ataluren 26 50 Frameshift p.Arg2401Leufs*9 109 Exon 51 skip 27 48–50 Frameshift c.(6912 + 1_6913-1)-(7309 + 1_1310-1)del p.Val2305Leufs*9 397 Exon 51 skip 28 5–6 Frameshift 29 49–52 Frameshift c.7099-?_7660+?del p.Glu2367Leufs*22 562 Exon 53 skip 30 6 Nonsense c.488G > A p.Trp163Ter 1 Ataluren 31 49–50 Frameshift p.Glu2367Leufs*22 211 Exon 51 skip 32 30 In-frame c.4072-?_4233+?del p.Ala1357_Lys1411del 162 33 34 Nonsense c.4839G > A p.Trp1613Ter 1 Ataluren 1 Deleted exon: deletion or absence of one or more exons. 2 Exon duplicated: repetition of one or more exons. 3 Exon with variant type: Number of variant exon type, this change can be deletion, duplication, insertion, missense, or nonsense 4 Variant type: A mutation or pathogenic variant frameshift, outframe or in-frame 5 DNA level change: change in DNA sequence 6 Amino acid change: one amino acid (building block of proteins) is replaced by a different amino acid 7 Length of mutated sequence: number of nucleotides that have changed in a DNA sequence 8 Potential Therapy: treatment that shows the ability to be effective in modifiying a disease Of the total cases, 15% had a duplication of one or more exons, usually in the range between the first exon and exon 20. The largest duplication comprised 9 exons (8–16), while the smallest duplication was of a single exon (exon 2) which occurred in only one patient. No deletions or duplications were detected in 10 cases. And point mutations (30%) were found by Next Generation Sequencing of the DMD gene. 73% of the cases were frameshift mutations, 21% were nonsense mutations and 3% were in-frame mutations. A single exon deletion (exon 30) was detected and cataloged as an in-frame variant (NM_004006.2 c.4072-_4233+?del; p. Ala1357_Lys1411del). A discrepancy between the genotype and the phenotype presented, given that it is a case of a 9-year-old boy, with a Duchenne muscular dystrophy phenotype and with a severe clinical condition due to loss of gait at an early age. It would be expected that the pathogenic variant being in-frame would lead to a mild DMB phenotype. 17 , 18 However, this case is an exception to the in-frame rule. Single nucleotide variants also known as point mutations 19 comprised 30% of all mutations in our cohort. These variants were evenly distributed in the gene, not specifically in hotspots. Notably, the most frequent of these types of mutations were nucleotide substitutions that generated premature stop codons (nonsense variants). Previous studies in individuals with point mutations were reported to be distributed along the DMD gene. 20 However, it is mentioned that in nonsense mutations, the position has important implications for predicting the phenotype. Therefore, at a certain position, it could give mild phenotypes as at the C-terminal end (exons 72 to 76) are not as detrimental since a truncated but partially functional protein is produced showing a BMD phenotype. 21 Two frameshift variants were detected that have not been previously reported, nor are they related to DMD -related variant databases. One was a deletion from exon 3 to 7 (NM_004006.2 c.94-?_649+?del;p.Phe32Metfs*13) with DMD phenotype, even with ambulation at 10 years of age. Another was a single nucleotide variant in exon 30 that generates a stop codon (NM_004006.3 c.4099dup) and makes a change in the p.Gln1367ProfsTer10 protein, with a severe DMD phenotype and loss of ambulation at 9 years of age. Another case of a single nucleotide variant was in exon 3 (NM_004006.4 c.177del), which makes a p.Gln60LysfsTer15 protein change that is reported in the CLINVAR 22 database but without functional evidence, therefore it is probably pathogenic. In this case with DMD phenotype, with elevated muscle enzymes, and even with ambulation at 11 years of age. These findings confirm that DMD presents genotypic heterogeneity and the possibility of discordance between genotype and phenotype in this disease. These new variants will be reported in the CLINVAR database as findings specific to the population studied. Elevated values of Creatinine Kinase (CPK), as well as Alanine and Aspartate Transaminase (ALT and AST), result from rupture and necrosis of muscle fibers. As they are used as biomarkers, they are a guideline for genetic testing. 23 In our study only 54.5% of subjects had CPK with a minimum value of 345 and a maximum of 11,570. Discussion The findings of this study underscore significant diagnostic delays in the identification of Duchenne muscular dystrophy in Guatemala. Symptom onset occurred before the age of five in 85% of cases, yet 60% were diagnosed after age six. This reflects a substantial gap between disease onset and diagnosis, likely attributable to limited access to molecular diagnostics, low awareness of neuromuscular disorders among healthcare providers, and insufficient public health policies addressing rare diseases. As Duchenne muscular dystrophy is a progressive disorder, delayed diagnosis has critical implications, preventing timely intervention with supportive care and emerging disease-modifying treatments. The study confirms that the mutational spectrum of Guatemalan Duchenne muscular dystrophy patients is consistent with global trends, with deletions (55%) being the most prevalent mutation type, primarily clustered within the exon 45–55 hotspot. However, the observed frequency of nonsense mutations (21%) is notably higher than the 10–15% reported in other populations. 7 , 24 This finding is particularly relevant for the potential application of premature termination codon-readthrough therapies, such as ataluren, which could offer treatment options for a considerable proportion of patients. 25 , 26 The presence of two novel pathogenic variants in this cohort reinforces the importance of region-specific genetic research. While most deletions were in known hotspots, these novel variants highlight the genetic diversity in the Guatemalan population and the potential for previously unreported mutations. Such findings emphasize the need for population-wide genetic screening to capture the full spectrum of DMD gene alterations. One of the key challenges identified is the lack of a national epidemiological surveillance system for Duchenne muscular dystrophy. Currently, there is no systematic registry of diagnosed cases, hindering effective disease monitoring and the development of national health strategies. Without a robust registry, estimating true disease prevalence and evaluating the long-term impact of therapeutic interventions remain difficult. Establishing a national Duchenne muscular dystrophy registry would facilitate patient follow-up, improve access to emerging treatments, and support clinical trial recruitment. Furthermore, the study highlights disparities in healthcare access, particularly between urban and rural populations. More than 60% of patients were from rural areas, where healthcare resources are often limited. This geographical disparity contributes to later diagnoses and reduced access to genetic testing. Cost-effective diagnostic methods, such as MLPA for detecting exon deletions and duplications, could be widely implemented to bridge this gap. However, cases with point mutations or deep intronic variants require next-generation sequencing, which remains inaccessible to many Guatemalan patients due to financial and logistical constraints. From a therapeutic perspective, 49% of cases in this study were eligible for exon-skipping therapies targeting exons 44, 45, 51, and 53, which are currently in clinical use or trials 27 , 28 , 29 The development of exon-skipping therapies represents a significant advancement in precision medicine, allowing mutation-specific treatment for a subset of Duchenne muscular dystrophy patients. Additionally, gene therapy approaches, such as micro-dystrophin replacement strategies and CRISPR-Cas9 genome editing, are in advanced clinical trials 30 , 31 Expanding access to these therapies in Guatemala will require coordinated efforts at the governmental and international levels, including regulatory approvals and funding initiatives. The study also reinforces the role of genetic counselling in patient management. Many affected families lack access to adequate genetic counselling, leading to misunderstandings about disease inheritance, recurrence risks, and reproductive options. Expanding genetic counselling services should be a priority to support affected families and inform clinical decision-making. Conclusion This study provides the first systematic genetic and clinical characterisation of Duchenne muscular dystrophy in Guatemala. The findings confirm significant diagnostic delays and substantial genetic heterogeneity, including two novel variants. A high proportion of nonsense mutations suggests that premature termination codon-readthrough therapies could benefit many patients. Nearly half of the cases were eligible for exon-skipping therapies, reinforcing the need for targeted treatments. The absence of a national patient registry and limited access to genetic testing hinder timely diagnosis and treatment. Establishing a registry, improving diagnostic infrastructure, and increasing access to molecular therapies should be healthcare priorities. Genetic counseling services must also be expanded to better support affected families. Future research should focus on longitudinal follow-up, treatment responses, and the socio-economic impact of Duchenne muscular dystrophy in Guatemala. Addressing these challenges will require coordinated efforts at the national and international levels to improve patient outcomes and healthcare accessibility. Limitations: This study has several limitations. The sample size was relatively small (n = 33), limiting the generalisability of findings to the broader Guatemalan population. Additionally, case ascertainment relied on a convenience-based sampling approach, potentially underestimating true disease prevalence due to unreported or undiagnosed cases, particularly in rural areas with limited healthcare access. Genetic testing was restricted to Multiplex Ligation-dependent Probe Amplification and NGS, which may not detect all pathogenic variants, such as deep intronic mutations or structural rearrangements. The reliance on a single bioinformatics pipeline could have led to the omission of complex variants. Moreover, access to molecular testing was limited, making it likely that some cases remain undiagnosed. This study was cross-sectional, providing a snapshot of disease prevalence and mutation distribution but lacking longitudinal data on disease progression, response to treatment, and long-term outcomes. Future studies should incorporate follow-up data to better assess clinical trajectories and the impact of therapeutic interventions. Finally, the lack of a national Duchenne muscular dystrophy registry restricts epidemiological surveillance and complicates patient follow-up. Establishing a registry would enable more accurate prevalence estimates, facilitate clinical trial recruitment, and improve long-term patient management. Declarations Ethical Approval The study was authorized by the Ethics Committee of the General Hospital 'San Juan de Dios', number CI-073/2, 024. Written informed consent was obtained from the patient's parents. Declaration of interests AAk is a consultants for NESTA. MO, EK, GR, GS,J C, SDLV declare no conflict of interest. Funding statement AAK is funded by The Motor Neurone Disease Association (MNDA), NIHR Maudsley Biomedical Research Centre and ALS Association Milton Safenowitz Research Fellowship, the Darby Rimmer MND Foundation, LifeArc, and the Dementia Consortium. AAK is supported by the UK Dementia Research Institute through UK DRI Ltd, principally funded by the Medical Research Council. Author Contributions MO conceived and planned the study. MO created the bioinformatics pipeline for analysis. MO, EK, GR, GS,J C, SDLV prepared phenotypic data. MO, EK, and GR did the statistical analysis and prepared the figures and tables. EK,GR,GS,JC,SDLV helped in sample collection and provided whole genome sequence data, analysis and intellectual input for data interpretation. AAK provided intellectual input for data interpretation. MO EK,GR,GS,JC,SDLV wrote the first draft of the manuscript. All authors reviewed and approved the final manuscript. Acknowledgments The lead author would like to thank all co-author for their contributions, and Dr. José M. Moreno, Genetics Unit, University of Guadalajara. Jalisco, Mexico and PTC Therapeutics, especially MSc. Heydi Eleana Mateus, MSc. Natalia Morales and MCs. Zulema Cruz, and to the patients who kindly agreed to participate in this study. Data availability statement Data access will require the completion of a data access request to the crossponding auther. References Duchenne GBA Paralysie musculaire pseudohypertrophique ou paralysie myo- sclérosique. Archives Générales de Médecine 1868; 1–144. https://wellcomecollection.org/works/fkv5yrjv Huamán-Dianderas F, Guevara-Fujita M, Málaga D et al (2019) Amplificación múltiple dependiente de ligación por sondas. 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J Comp Eff Res 11(3):139–155 [citado 24 Sept 2024]. https://doi.org/10.2217/cer-2021-0196 Patterson G, Conner H, Groneman M et al (2023) Duchenne muscular dystrophy: Current treatment and emerging exon skipping and gene therapy approach. Eur J Pharmacol 947:175675. https://doi.org/10.1016/j.ejphar.2023.175675 Fortunato F, Rossi R, Falzarano M et al (2021) Innovative therapeutic approaches for Duchenne Muscular Dystrophy. J Clin Med 10(4):820. https://doi.org/10.3390/jcm10040820 Takeda S, Clemens P, Hoffman E (2021) Exon-Skipping in Duchenne Muscular Dystrophy. J Nneuromus Dis 8(s2):S343–S358. https://doi.org/10.3233/JND-210682 Mendell J, Proud C, Zaidman C et al (2024) Practical considerations for Delandistrogene Moxeparvovec gene therapy in patients with Duchenne muscular dystrophy. Pediatr Neurol 153:11–18. https://doi.org/10.1016/j.pediatrneurol.2024.01.003 Happi C, Lamothe G, Tremblay G et al (2022) CRISPR-Cas9 gene therapy for Duchenne muscular dystrophy. Neurotherapeutics 19(3):931–941. https://doi.org/10.1007/s13311-022-01197-9 Footnotes Coding region of the gene Genes encoding the physical characteristics of an organism Characteristics observed as a result o f gene expression Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5556317","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":418618236,"identity":"fe5d8bd5-2efd-47d2-9eb3-bd924725a88d","order_by":0,"name":"Marcela Orozco","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFElEQVRIiWNgGAWjYDCCAzAGO5zRACQMLIjQwgxj8ICEDCRI0SKRACZx6uC7ffgB042ae/L8zMwPH1dU1MnzSz6/uuFHgQQDf3t3AjYtkufSDJhzjhUbzmxmMzY8c4bNcObsnLKbPUCHSZw5uwGbFoMzDEAtbAkJBocZzCQb23gSDG7npN3gAWoxkMjFoYX9A3POv4QE+8Ps34BaJBIMbp5Ju/kHrxYeA+bcNqAtzDwgWwwSDG6wH7uNzxbJMzwFh3P7EgxnHOYpNmw4k2A4syeH7baMgQQPLr/wnWHf+DjnW4I8f3v7xocNoBBjP/7s5ps/NnL87b1YtYDAATQ+jwGYxKUcG2B/QIrqUTAKRsEoGP4AAD/bXhMw2DItAAAAAElFTkSuQmCC","orcid":"","institution":"Neuromuscular and Rare Diseases Unit, Department of Neurology and Neurosciences, Hospital General ´San Juan de Dios´,","correspondingAuthor":true,"prefix":"","firstName":"Marcela","middleName":"","lastName":"Orozco","suffix":""},{"id":418618237,"identity":"67c429e8-b009-4ecc-9a16-e8bc07f10172","order_by":1,"name":"Edgar Kestler","email":"","orcid":"","institution":"Centre for Epidemiological Research in Sexual and Reproductive Health, Hospital General ´San Juan de Dios","correspondingAuthor":false,"prefix":"","firstName":"Edgar","middleName":"","lastName":"Kestler","suffix":""},{"id":418618238,"identity":"ba160039-a93f-4921-9fcc-176be7a3b756","order_by":2,"name":"Gerardo Ramírez","email":"","orcid":"","institution":"Department of Neurology and Neurosciences, Hospital General ´San Juan de Dios","correspondingAuthor":false,"prefix":"","firstName":"Gerardo","middleName":"","lastName":"Ramírez","suffix":""},{"id":418618239,"identity":"a79d4b1c-70f9-4d62-9eb7-8f008e7729b6","order_by":3,"name":"Gabriel Silva","email":"","orcid":"","institution":"Genetics Unit, Obras Sociales del Santo Hermano Pedro","correspondingAuthor":false,"prefix":"","firstName":"Gabriel","middleName":"","lastName":"Silva","suffix":""},{"id":418618240,"identity":"ae72e2db-312d-4e50-a178-36195ef0964b","order_by":4,"name":"Julio Cabrera","email":"","orcid":"","institution":"Genetics Unit, Hospital Roosevelt","correspondingAuthor":false,"prefix":"","firstName":"Julio","middleName":"","lastName":"Cabrera","suffix":""},{"id":418618241,"identity":"8a4e3c1e-2e62-439c-b225-b8ace3361a37","order_by":5,"name":"Sofia De la Vega","email":"","orcid":"","institution":"Foundation for the Welfare of the Disabled (FUNDABIEM)","correspondingAuthor":false,"prefix":"","firstName":"Sofia","middleName":"De la","lastName":"Vega","suffix":""},{"id":418618242,"identity":"47a75b5a-4040-4ad7-8994-27c5f2fc4418","order_by":6,"name":"Ahmad Al Khleifat","email":"","orcid":"","institution":"Maurice Wohl Clinical Neuroscience Institute, King’s College","correspondingAuthor":false,"prefix":"","firstName":"Ahmad","middleName":"Al","lastName":"Khleifat","suffix":""}],"badges":[],"createdAt":"2024-12-01 00:08:07","currentVersionCode":2,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-5556317/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-5556317/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78912398,"identity":"2486821b-be19-4841-9f85-d650ac960bb9","added_by":"auto","created_at":"2025-03-20 17:22:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":725256,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5556317/v2/50fcd03f-2c20-4db3-8fad-c8089555833d.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"Genetic and Clinical Landscape of Duchenne Muscular Dystrophy in Guatemala: Insights from a National Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDuchenne Muscular Dystrophy is a severe, progressive, and disabling neuromuscular disease, one of the most common muscular dystrophies.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e It is considered an inherited, recessive, X-linked (Xp21) myopathy caused by mutations in the DMD gene. \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e The reported worldwide incidence is 1:3 per 600-9,300 live births.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e The worldwide prevalence has been estimated at 3.6 per 100,000 population but varies by geographic area.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCountries with a high Economic Development Index (HEDI) tend to have more robust epidemiological data, reflecting better access to diagnostic technologies and disease surveillance systems. In contrast, countries with medium or low EDI often lack such data, highlighting significant limitaions. Nowhere is this more evident than in Guatemala, where no prevalence data for Duchenne muscular dystrophy is available. By comparison, Chile, a country with more developed healthcare infrastructure, reports a prevalence of 11.51 per 100,000 men under 30 years, illustrating the regional variation in both disease burden and the ability to measure it, illustrating the regional variation in both disease burden and detection capacity \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Another reported and related factor is the economic burden of this disease as it progresses to the critical stages of the disease, with the cost of the disease increasing by up to 16 times.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe molecular basis of DMD is complex, over 7,000 variants in the DMD gene are thought to be associated with Duchenne Muscular Dystrophy, with deletions and duplications of exons being the most frequent variants at 80% and 20% with point gene variants.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e The DMD gene is 2.4 Mb in size and harbors 79 exons. This gene produces the protein Dystrophin which is part of the dystrophin-associated protein complex with a structural function in helping to stabilize the sarcolemma and protecting muscle fibers from damage and necrosis caused by prolonged contraction. When reduced but functional dystrophin is present it is considered Becker Muscular Dystrophy (BMD-OMIM #300376) which carries a better prognosis for the patient. \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe structural and functional variations of dystrophin depend on the type of mutation in the DMD gene, which can range from an affected but functional protein to a non-functional or even absent protein. As a result, they can lead to different forms and severities of the disease. Identifying the mutational spectrum of the DMD gene is important to guide and apply feasible therapies that are mutation-specific. There is a lack of knowledge about the mutation profile in Guatemalan patients. Identifying the spectrum in the Guatemalan population is necessary to determine if they are eligible for treatment. \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCurrently, Guatemala lacks an epidemiological surveillance system for neuromuscular and rare diseases and the genetic profile of patients affected by DMD is unknown. Many cases, especially in rural areas, are under-diagnosed. This article aims to present the national urban-rural results of an epidemiological, socio-demographic, clinical characteristics, and mutational spectrum in the Guatemalan population.\u003c/p\u003e \u003cp\u003eUnderstanding the genetic diversity of Duchenne muscular dystrophy is crucial for several reasons. It provides insights into genetic risk factors, offering valuable knowledge about previously unknown aspects of the disorder. Moreover, studying DMD in diverse populations helps to develop more inclusive and precise genetic tests, diagnostics, and therapies. Without expanding genetic research beyond Western populations, there is a significant risk of overlooking variants critical to understanding DMD in other ethnic and regional groups.\u003c/p\u003e \u003cp\u003eCurrently, there is limited knowledge of the genetic profile of DMD in Guatemala and other Central American populations. Most genetic studies of DMD focus on regions with robust healthcare infrastructure, leaving gaps in our understanding of how the disease manifests in lower-resource settings. This study seeks to address these gaps by characterising the genetic and clinical features of DMD in Guatemala, a population with a distinct socio-economic and genetic background. By analysing the prevalence, mutational spectrum, and clinical presentation of DMD in this region, we aim to identify novel genetic variants and assess whether previously known mutations are similarly implicated. Understanding these region-specific genetic factors could provide new insights into the disease mechanism and support the development of targeted therapies and diagnostic tools, contributing to a more comprehensive global understanding of DMD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eDuring 16 months (October 2022 to January 2024), 33 (100%) active cases of any age, with clinical suspicion of DMD were detected from two national reference hospitals (73%) most important in the country, from the Social Security hospital (9%), Foundation for the Welfare of the Disabled (FUNDABIEM) (15%) and private clinic (3%). Patients with clinical suspicion of DMD, but with negative molecular test were excluded. A follow-up, cross-sectional, non-probability, convenience-based, analytical study was performed.\u003c/p\u003e \u003cp\u003eFor variant detection, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed by probe denaturation, ligation, Polymerase Chain Reaction (PCR) amplification, and fragment separation by capillary electrophoresis, using MRC Holland probes P034 and P035 that analyze all exons (79 exons), for deletions or duplications of the DMD gene. In cases where MLPA did not detect any deletions or duplications, sequencing of the gene was performed. Coffalyser.net software was used for bioinformatics analysis of the data obtained.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e For DNA sequencing analysis, the DNB-SEQ400 next-generation mass sequencer was used. \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e The analysis was aimed at identifying variants included in exonic regions or splice regions, insertions, and small deletions. Genetic testing was performed by the GenCell Gen\u0026eacute;tica Avanzada laboratory in Bogot\u0026aacute;, Colombia as well as the logistics of transporting blood (79%) and saliva (21%) samples.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData management and analysis\u003c/h3\u003e\n\u003cp\u003eA data collection form was developed that included demographic, social, economic, clinical, electrodiagnostic, and molecular laboratory studies. All data was recorded and re-recorded for recording errors or inconsistencies. This was carried out in the statistical program EPINFO V6.0 .\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e and descriptive statistics were obtained, with a confidence interval of 95%. The analysis and interpretation of genetic variants were performed using the open-access, web-based tool \"DMD Open-access Variant Explore (DOVE)\" \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e providing information on amino acid change, functional predictions at the protein level, length of the mutated sequence, and molecular eligibility for treatment based on specific variants to correct the reading frame.\u003c/p\u003e\n\u003ch3\u003eWhole-genome sequencing\u003c/h3\u003e\n\u003cp\u003eDNA was isolated from venous blood using standard methods. DNA concentration was set at 100ng/ul as measured by fluorimeter. DNA integrity was assessed using gel electrophoresis. All samples were sequenced using Illumina\u0026rsquo;s FastTrack services (San Diego, CA, USA) on the Illumina HiSeq 2000 (100bp paired-end reads) and HiSeqX platforms (150bp paired end reads), using PCR-free library preparations. Binary sequence alignment/map formats (BAM) were generated for each individual. The Project MinE genomes were aligned with Isaac (Illumina) to hg19.\u003c/p\u003e\n\u003ch3\u003eQuality Control\u003c/h3\u003e\n\u003cp\u003eSample mismatch was tested using sex checks, where genetic sex was compared to reported gender. After quality control, the full set of gVCFs were merged together by first converting the gVCFs to Plink format and then merging all files together. This generated a single dataset containing all variant sites across all individuals. Non-autosomal chromosome and multi-allelic variants were excluded from pilot analyses.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThirty-seven (37) cases with clinically suspected Duchenne muscular dystrophy were detected and referred from different health institutions participating in the study. Four cases had negative genetic test results and were therefore excluded. This left 33 genetically confirmed cases with Duchenne muscular dystrophy that are part of this analysis. Again, it is confirmed that all genetically positive cases were male as DMD is an X-linked disease.\u003c/p\u003e \u003cp\u003eThe prevalence found for this study cohort was 0.61 per 100,000 men under 30 years (33/5.395,769 denominator according to projections based on the last census of Guatemala 2018). \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Seventy-six percent of the cases detected for the first time were between six and ten years old, 48% were late school leavers, 55% were of middle socio-economic status, 15% were of kinship and 61% were from rural areas. Eighty-five percent of the cases started their symptomatology before the age of 5 years, but unfortunately, 60% of the cases were diagnosed after the age of 6 years.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the details of the molecular variants of the 33 cases detected. 23 (70%) cases presented deletion and duplication detected by MLPA, with deletions of one or more exons\u003ca class=\"FNLink\" href=\"#Fn1\" id=\"#FNLinkFn1\"\u003e\u003c/a\u003e (55%) being the most frequent pathogenic variant detected, most of them (72%) found in one of the hot spots from exons 45 to 55. Six cases had deletions of a single exon, four of which were exon 45, one case of exon 50, and one case of exon 30, which was the only one found within the in-frame.\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\u003eSpectrum of mutations found in patients with DMD in Guatemala\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\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\u003eDeleted exon \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eExon duplicated\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eExon with variant type \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVariant type \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDNA level change \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAmino acid change \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLength of mutated sequence \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePotential Therapy \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\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\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45\u0026ndash;50\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Glu2147Leu*9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 51 skip\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\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.32\u0026thinsp;\u0026minus;\u0026thinsp;2_93+?dup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Phe32Metfs*15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\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\u003e46\u0026ndash;55\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.6615-?_8217+?del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Leu2206Thrfs*24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1603\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 45 skip\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\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.4099dup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Gln1367ProfsTer10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\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\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.6986dup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Leu2330AlafsTer10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\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\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.5704_5707del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Ser1902TyfsTer10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\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\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u0026ndash;16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.650-?_1992+?dup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep. ?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\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\u003e3\u0026ndash;7\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.94-?_649+?del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Phe32Metfs*13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e556\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 8 skip\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\u003e45\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.6439-?_8390+?del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Glu2147Alafs*17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 44 skip\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\u003e45\u0026ndash;56\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Glu2147Valfs*8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1952\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 44 skip\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\u003e45\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.6439-?_8390+?del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Glu2147Alafs*17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 44 skip\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\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.5641C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Gln1881Ter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAtaluren\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\u003e49\u0026ndash;50\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.7099-?_7309\u0026thinsp;+\u0026thinsp;del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Glu2367Leufs*9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 51 skip\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\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.354G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Trp118Ter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAtaluren\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\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.354G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Trp118Ter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAtaluren\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\u003e45\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.6439-?_8390+?del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Glu2147Alafs*17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\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\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u0026ndash;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep. ?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\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\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.354G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Trp118Ter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAtaluren\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\u003e46\u0026ndash;51\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Leu2206Glnfs*23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e928\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 45 skip\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\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u0026ndash;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\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\u003e46\u0026ndash;50\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.6615-?_7309\u0026thinsp;+\u0026thinsp;del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Arg2205Serfs*16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e695\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 51 skip\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\u003e5\u0026ndash;7\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.265-?_649+?del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Val89Metfs*13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e385\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 8 skip\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\u003e10\u0026ndash;11\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.961-?_1331+?del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.His321Phefs*3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e371\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 12 skip\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\u003e45\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.6439-?_8390+?del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Glu2147Alafs*17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 44 skip\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.7683G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Trp2561Ter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAtaluren\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Arg2401Leufs*9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 51 skip\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48\u0026ndash;50\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.(6912\u0026thinsp;+\u0026thinsp;1_6913-1)-(7309\u0026thinsp;+\u0026thinsp;1_1310-1)del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Val2305Leufs*9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e397\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 51 skip\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u0026ndash;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49\u0026ndash;52\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.7099-?_7660+?del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Glu2367Leufs*22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e562\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 53 skip\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.488G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Trp163Ter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAtaluren\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49\u0026ndash;50\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\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Glu2367Leufs*22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eExon 51 skip\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\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\u003eIn-frame\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.4072-?_4233+?del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Ala1357_Lys1411del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e162\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ec.4839G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep.Trp1613Ter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAtaluren\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Deleted exon: deletion or absence of one or more exons.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Exon duplicated: repetition of one or more exons.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Exon with variant type: Number of variant exon type, this change can be deletion, duplication, insertion, missense, or nonsense\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Variant type: A mutation or pathogenic variant frameshift, outframe or in-frame\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e DNA level change: change in DNA sequence\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Amino acid change: one amino acid (building block of proteins) is replaced by a different amino acid\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Length of mutated sequence: number of nucleotides that have changed in a DNA sequence\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Potential Therapy: treatment that shows the ability to be effective in modifiying a disease\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOf the total cases, 15% had a duplication of one or more exons, usually in the range between the first exon and exon 20. The largest duplication comprised 9 exons (8\u0026ndash;16), while the smallest duplication was of a single exon (exon 2) which occurred in only one patient. No deletions or duplications were detected in 10 cases. And point mutations (30%) were found by Next Generation Sequencing of the \u003cem\u003eDMD\u003c/em\u003e gene. 73% of the cases were frameshift mutations, 21% were nonsense mutations and 3% were in-frame mutations.\u003c/p\u003e \u003cp\u003eA single exon deletion (exon 30) was detected and cataloged as an in-frame variant (NM_004006.2 c.4072-_4233+?del; p. Ala1357_Lys1411del). A discrepancy between the genotype\u003ca class=\"FNLink\" href=\"#Fn2\" id=\"#FNLinkFn2\"\u003e\u003c/a\u003e and the phenotype\u003ca class=\"FNLink\" href=\"#Fn3\" id=\"#FNLinkFn3\"\u003e\u003c/a\u003e presented, given that it is a case of a 9-year-old boy, with a Duchenne muscular dystrophy phenotype and with a severe clinical condition due to loss of gait at an early age. It would be expected that the pathogenic variant being in-frame would lead to a mild DMB phenotype.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e However, this case is an exception to the in-frame rule.\u003c/p\u003e \u003cp\u003eSingle nucleotide variants also known as point mutations \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e comprised 30% of all mutations in our cohort. These variants were evenly distributed in the gene, not specifically in hotspots. Notably, the most frequent of these types of mutations were nucleotide substitutions that generated premature stop codons (nonsense variants). Previous studies in individuals with point mutations were reported to be distributed along the \u003cem\u003eDMD\u003c/em\u003e gene. \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e However, it is mentioned that in nonsense mutations, the position has important implications for predicting the phenotype. Therefore, at a certain position, it could give mild phenotypes as at the C-terminal end (exons 72 to 76) are not as detrimental since a truncated but partially functional protein is produced showing a BMD phenotype. \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTwo frameshift variants were detected that have not been previously reported, nor are they related to \u003cem\u003eDMD\u003c/em\u003e-related variant databases. One was a deletion from exon 3 to 7 (NM_004006.2 c.94-?_649+?del;p.Phe32Metfs*13) with DMD phenotype, even with ambulation at 10 years of age. Another was a single nucleotide variant in exon 30 that generates a stop codon (NM_004006.3 c.4099dup) and makes a change in the p.Gln1367ProfsTer10 protein, with a severe DMD phenotype and loss of ambulation at 9 years of age.\u003c/p\u003e \u003cp\u003eAnother case of a single nucleotide variant was in exon 3 (NM_004006.4 c.177del), which makes a p.Gln60LysfsTer15 protein change that is reported in the CLINVAR \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e database but without functional evidence, therefore it is probably pathogenic. In this case with DMD phenotype, with elevated muscle enzymes, and even with ambulation at 11 years of age. These findings confirm that DMD presents genotypic heterogeneity and the possibility of discordance between genotype and phenotype in this disease. These new variants will be reported in the CLINVAR database as findings specific to the population studied. Elevated values of Creatinine Kinase (CPK), as well as Alanine and Aspartate Transaminase (ALT and AST), result from rupture and necrosis of muscle fibers. As they are used as biomarkers, they are a guideline for genetic testing. \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e In our study only 54.5% of subjects had CPK with a minimum value of 345 and a maximum of 11,570.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings of this study underscore significant diagnostic delays in the identification of Duchenne muscular dystrophy in Guatemala. Symptom onset occurred before the age of five in 85% of cases, yet 60% were diagnosed after age six. This reflects a substantial gap between disease onset and diagnosis, likely attributable to limited access to molecular diagnostics, low awareness of neuromuscular disorders among healthcare providers, and insufficient public health policies addressing rare diseases. As Duchenne muscular dystrophy is a progressive disorder, delayed diagnosis has critical implications, preventing timely intervention with supportive care and emerging disease-modifying treatments.\u003c/p\u003e \u003cp\u003eThe study confirms that the mutational spectrum of Guatemalan Duchenne muscular dystrophy patients is consistent with global trends, with deletions (55%) being the most prevalent mutation type, primarily clustered within the exon 45\u0026ndash;55 hotspot. However, the observed frequency of nonsense mutations (21%) is notably higher than the 10\u0026ndash;15% reported in other populations.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e This finding is particularly relevant for the potential application of premature termination codon-readthrough therapies, such as ataluren, which could offer treatment options for a considerable proportion of patients.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe presence of two novel pathogenic variants in this cohort reinforces the importance of region-specific genetic research. While most deletions were in known hotspots, these novel variants highlight the genetic diversity in the Guatemalan population and the potential for previously unreported mutations. Such findings emphasize the need for population-wide genetic screening to capture the full spectrum of \u003cem\u003eDMD\u003c/em\u003e gene alterations.\u003c/p\u003e \u003cp\u003eOne of the key challenges identified is the lack of a national epidemiological surveillance system for Duchenne muscular dystrophy. Currently, there is no systematic registry of diagnosed cases, hindering effective disease monitoring and the development of national health strategies. Without a robust registry, estimating true disease prevalence and evaluating the long-term impact of therapeutic interventions remain difficult. Establishing a national Duchenne muscular dystrophy registry would facilitate patient follow-up, improve access to emerging treatments, and support clinical trial recruitment.\u003c/p\u003e \u003cp\u003eFurthermore, the study highlights disparities in healthcare access, particularly between urban and rural populations. More than 60% of patients were from rural areas, where healthcare resources are often limited. This geographical disparity contributes to later diagnoses and reduced access to genetic testing. Cost-effective diagnostic methods, such as MLPA for detecting exon deletions and duplications, could be widely implemented to bridge this gap. However, cases with point mutations or deep intronic variants require next-generation sequencing, which remains inaccessible to many Guatemalan patients due to financial and logistical constraints.\u003c/p\u003e \u003cp\u003eFrom a therapeutic perspective, 49% of cases in this study were eligible for exon-skipping therapies targeting exons 44, 45, 51, and 53, which are currently in clinical use or trials\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e The development of exon-skipping therapies represents a significant advancement in precision medicine, allowing mutation-specific treatment for a subset of Duchenne muscular dystrophy patients. Additionally, gene therapy approaches, such as micro-dystrophin replacement strategies and CRISPR-Cas9 genome editing, are in advanced clinical trials\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e Expanding access to these therapies in Guatemala will require coordinated efforts at the governmental and international levels, including regulatory approvals and funding initiatives.\u003c/p\u003e \u003cp\u003eThe study also reinforces the role of genetic counselling in patient management. Many affected families lack access to adequate genetic counselling, leading to misunderstandings about disease inheritance, recurrence risks, and reproductive options. Expanding genetic counselling services should be a priority to support affected families and inform clinical decision-making.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study provides the first systematic genetic and clinical characterisation of Duchenne muscular dystrophy in Guatemala. The findings confirm significant diagnostic delays and substantial genetic heterogeneity, including two novel variants. A high proportion of nonsense mutations suggests that premature termination codon-readthrough therapies could benefit many patients. Nearly half of the cases were eligible for exon-skipping therapies, reinforcing the need for targeted treatments.\u003c/p\u003e \u003cp\u003eThe absence of a national patient registry and limited access to genetic testing hinder timely diagnosis and treatment. Establishing a registry, improving diagnostic infrastructure, and increasing access to molecular therapies should be healthcare priorities. Genetic counseling services must also be expanded to better support affected families.\u003c/p\u003e \u003cp\u003eFuture research should focus on longitudinal follow-up, treatment responses, and the socio-economic impact of Duchenne muscular dystrophy in Guatemala. Addressing these challenges will require coordinated efforts at the national and international levels to improve patient outcomes and healthcare accessibility.\u003c/p\u003e"},{"header":"Limitations:","content":"\u003cp\u003eThis study has several limitations. The sample size was relatively small (n\u0026thinsp;=\u0026thinsp;33), limiting the generalisability of findings to the broader Guatemalan population. Additionally, case ascertainment relied on a convenience-based sampling approach, potentially underestimating true disease prevalence due to unreported or undiagnosed cases, particularly in rural areas with limited healthcare access.\u003c/p\u003e \u003cp\u003eGenetic testing was restricted to Multiplex Ligation-dependent Probe Amplification and NGS, which may not detect all pathogenic variants, such as deep intronic mutations or structural rearrangements. The reliance on a single bioinformatics pipeline could have led to the omission of complex variants. Moreover, access to molecular testing was limited, making it likely that some cases remain undiagnosed.\u003c/p\u003e \u003cp\u003eThis study was cross-sectional, providing a snapshot of disease prevalence and mutation distribution but lacking longitudinal data on disease progression, response to treatment, and long-term outcomes. Future studies should incorporate follow-up data to better assess clinical trajectories and the impact of therapeutic interventions.\u003c/p\u003e \u003cp\u003eFinally, the lack of a national Duchenne muscular dystrophy registry restricts epidemiological surveillance and complicates patient follow-up. Establishing a registry would enable more accurate prevalence estimates, facilitate clinical trial recruitment, and improve long-term patient management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eEthical Approval\u003c/h2\u003e \u003cp\u003e The study was authorized by the Ethics Committee of the General Hospital 'San Juan de Dios', number CI-073/2, 024. Written informed consent was obtained from the patient's parents.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eDeclaration of interests\u003c/h2\u003e \u003cp\u003eAAk is a consultants for NESTA. MO, EK, GR, GS,J C, SDLV declare no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding statement\u003c/h2\u003e \u003cp\u003eAAK is funded by The Motor Neurone Disease Association (MNDA), NIHR Maudsley Biomedical Research Centre and ALS Association Milton Safenowitz Research Fellowship, the Darby Rimmer MND Foundation, LifeArc, and the Dementia Consortium. AAK is supported by the UK Dementia Research Institute through UK DRI Ltd, principally funded by the Medical Research Council.\u003c/p\u003e\u003ch2\u003eAuthor Contributions\u003c/h2\u003e \u003cp\u003eMO conceived and planned the study. MO created the bioinformatics pipeline for analysis. MO, EK, GR, GS,J C, SDLV prepared phenotypic data. MO, EK, and GR did the statistical analysis and prepared the figures and tables. EK,GR,GS,JC,SDLV helped in sample collection and provided whole genome sequence data, analysis and intellectual input for data interpretation. AAK provided intellectual input for data interpretation. MO EK,GR,GS,JC,SDLV wrote the first draft of the manuscript. All authors reviewed and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eThe lead author would like to thank all co-author for their contributions, and Dr. Jos\u0026eacute; M. Moreno, Genetics Unit, University of Guadalajara. Jalisco, Mexico and PTC Therapeutics, especially MSc. Heydi Eleana Mateus, MSc. Natalia Morales and MCs. Zulema Cruz, and to the patients who kindly agreed to participate in this study.\u003c/p\u003e\u003ch2\u003eData availability statement\u003c/h2\u003e \u003cp\u003eData access will require the completion of a data access request to the crossponding auther.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDuchenne GBA Paralysie musculaire pseudohypertrophique ou paralysie myo- scl\u0026eacute;rosique. 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Neurotherapeutics 19(3):931\u0026ndash;941. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s13311-022-01197-9\u003c/span\u003e\u003cspan address=\"10.1007/s13311-022-01197-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Footnotes","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e Coding region of the gene\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e Genes encoding the physical characteristics of an organism\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e Characteristics observed as a result o\u003c/span\u003e\u003cdiv id=\"Par33\" class=\"Para\"\u003ef gene expression\u003c/div\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5556317/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5556317/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDuchenne muscular dystrophy (DMD) is a severe X-linked disorder caused by mutations in the \u003cem\u003eDMD\u003c/em\u003e gene, with a global prevalence of 3.6 per 100,000 people. Despite its well-documented genetic basis, no previous studies have characterised DMD in Guatemala. We analysed 33 genetically confirmed cases to estimate prevalence, describe the mutation spectrum, and assess clinical features. Prevalence was 0.61 per 100,000 men under 30. Symptoms began before age 5 in 85% of cases, yet 60% were diagnosed after age 6, highlighting significant diagnostic delays. Deletions were the most common mutation (55%), followed by point mutations (30%) and duplications (15%), with two novel variants identified. Most deletions clustered in the exon 45\u0026ndash;55 hotspot. Nearly half of the cases were eligible for exon-skipping therapies. These findings reveal genetic heterogeneity in the Guatemalan population, substantial delays in diagnosis, and the need for improved access to genetic testing, targeted treatments, and a national DMD registry.\u003c/p\u003e","manuscriptTitle":"Genetic and Clinical Landscape of Duchenne Muscular Dystrophy in Guatemala: Insights from a National Study","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-03-20 17:06:08","doi":"10.21203/rs.3.rs-5556317/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2025-02-20 14:25:28","doi":"10.21203/rs.3.rs-5556317/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1ccd4e04-c4ee-4cdb-9d98-d371de56f3ce","owner":[],"postedDate":"March 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":44634318,"name":"Biological sciences/Genetics"},{"id":44634319,"name":"Health sciences/Diseases"},{"id":44634320,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-02-20T14:25:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-20 17:06:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-5556317","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5556317","identity":"rs-5556317","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}