eP271 - Disease-causing variants in hereditary neuromuscular disorder genes in an ethnically diverse Pakistani population - Experience from an Academic Medical Centre

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Introduction: Neuromuscular disorders (NMD) are a broad group of clinically heterogeneous disorders, largely classified as neuropathies, myopathies, muscular dystrophies and myasthenic syndromes. These sub-classes are further divided into several subtypes, depending on the involved causative gene and affected proteins encoded by these genes. This heterogeneous group of disorders may be inherited in autosomal recessive, autosomal dominant and X-linked fashion, with over 500 implicated genes. (Ankala et al., 2014; Chae et al., 2015) The most commonly seen disorders in the pediatric age group are Spinal Muscular Atrophy and Dystronipathies, testing for which is locally available. Other disorders, which require more specialized diagnostic testing such as Next Generation Sequencing (NGS) are harder to diagnose.Objective: To study the clinical and genetic profiles of patients presenting for evaluation of a hereditary neuromuscular disorder, excluding SMA and Dystrophinopathies.Methods: This is a retrospective chart review of patients seen in the Neurology Clinic and referred to the Genetics Clinic with a suspected hereditary neuromuscular disorder, between 2015 and 2020 at the Aga Khan University Hospital, Karachi. The genetic testing for these patients included NGS based single gene sequencing as part of a research collaboration, NGS based multi-gene panel and whole exome sequencing at multiple CAP and CLIA accredited commercial genetics laboratories.Result and Discussion: A total of 75 pediatric and adult patients evaluated in our Neurology and Genetics Clinic went ahead with genetic testing. 39 tested positive showing Pathogenic or Likely Pathogenic variant[s] in genes associated with NMDs, matching both the clinical phenotype and the inheritance pattern. 29 patients had one or multiple variants of uncertain significance (VUS) and seven had a negative test result. From the 29 results harboring VUSs, 23 results remained truly inconclusive. However, we believe that six of the VUSs are actually disease causing, showing variant segregation with disease phenotype in the family, and following the disease inheritance pattern. Based on this, we showed how the diagnostic yield improved, from a 52% positive results to 60% positive results, based on the clinical interpretation of results, with the help of deep phenotyping and familial segregation studies. The result distribution and yield are summarized in Table 1. The results showed a spectrum of 26 different genes with distinct phenotypes of NMDs in 45 patients. The result distribution across the genotype is summarized in Figure 1. The three commonly seen phenotypes were, Limb Girdle Muscular Dystrophy (LMGD) characterized in 12 patients, followed by Collagenopathies characterized in seven patients and GNE-associated Myopathy in six patients. Delving into the positive result findings genotypes, the most common genes include, GNE (13%), DYSF (11%), COL6A2 (9%), FKTN (9%) and SGCB (7%), accounting for 49% (n = 22) positive results. In all four unrelated Fukuyama muscular dystrophy patients, FKTN variant: NM_001079802, Exon 9 c.920G>A, p.Arg307Gln was found in a homozygous state. We also observed, that out of the six unrelated GNE associated myopathy patients, only GNE variant: NM_001128227.2, Exon 12 c.2179G>A, p.Val727Met, was present in four patients, one harbored a homozygous variant and three harbored heterozygous variant, present alongside another diseasecause variant in GNE, in compound heterozygous state. These two variants may represent possible founder mutations in the Pakistani population.Conclusion: This data from a clinical setting in an ethnically diverse Pakistani patient population shows the genetic heterogeneity and the spectrum of associated phenotypes found in NMDs. 80% of the positive patients (36/45) of the patients had a diagnosis of an autosomal recessive NMD. It was also observed that 21% of the reported VUSs identified were likely to be disease-causing based on clinical interpretation, warranting the need for larger NMD focused studies in our population. Variants unique to our population need to be validated by further functional studies, to clarify which ones are indeed pathogenic. As our understanding of the underlying genetic etiology of NMD improves, precision medicine initiatives for treating NMDs will accelerate.

Original languageUndefined/Unknown
Publication statusPublished - 1 Apr 2021

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