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Gene and mutation spectrum among Iranian individuals with neuromuscular disorders: An 11-year consolidated overview

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Hereditary neuromuscular disorders (NMDs) are genetic condition characterized by clinical and genetic heterogeneity which makes identifying the underlying causative genes challenging. Severity and age of onset differ among individuals ranging from birth to adulthood. Clinical manifestations could range from muscle weakness, muscle atrophy, and ataxia to inability to walk or move. This study aims to retrospectively analyze the genetic results of 2029 individuals suspected of having neuromuscular disorders referred to our pathology and genetic center between 2013 and 2024 to get a view of genes and mutational spectrum among the Iranian patients with NMD.

Methods:
Multiple ligation probe amplification (MLPA) for PMP22 gene testing was conducted for 547 individuals with suspected Charcot-Marie-Tooth disease type 1A (CMT1A) using SALSA MLPA Probemix P033-B4 CMT1 test kit. Gene panel sequencing (GPS) or whole exome sequencing (WES) was performed for 1557 Individuals with suspected NMDs (including 76 negative results of PMP22 testing). Genome libraries were prepared by Agilent SureSelect Human All Exome V4, V5, V6, and V7 or Twist Human Core Exome Kits and performed using Illumina sequencers (HiSeq 2000/2500/4000 and NovaSeq 6000) according to the manufacturer's protocols. Following diagnosis, individuals were categorized into groups based on online neuromuscular gene table and their phenotypes.

Results:
Among the 547 individuals who underwent MLPA testing, 28% (153/547) were confirmed to have deletions or duplications in the PMP22 gene. Of these, 73% (112/153) had duplications associated with Charcot-Marie-Tooth disease type 1A (CMT1A).

In a cohort of 1557 individuals referred for WES or GPS, a diagnostic yield of 47% (727/1557) was achieved. Eight hundred-four pathogenic and likely pathogenic variants were identified, of which 25% (204/804) were novel. The majority of these variants were missense (43%), followed by frameshift (22%), stop-gain (19%), and splicing variants (11%). Copy number variants (CNVs) comprised 3% (24/804) of the reported variants. Most diagnosed single nucleotide variants were inherited by autosomal recessive mode of inheritance (78%), followed by autosomal dominant (15%), and X-linked (7%).

Phenotypic grouping revealed that dystrophies were the most prevalent phenotype (30%), followed by myopathies (14%), neuropathies (14%), neuromuscular junction diseases (NMJs) (6%), motor neuron diseases (MNDs) (6%), hereditary paraplegia (5%), hereditary ataxia (3%), and myotonic syndromes (2%). Notably, 131 (18%) individuals exhibited overlapping phenotypes that could not be categorized into a single group based on clinical characteristics alone.

The most commonly implicated genes within each phenotypic group were as follows: dystrophies were predominantly associated with CAPN3 (27%) and DMD (17%); myopathies with GNE (13%) and ETFDH (10%); neuropathies with GDAP1 (10%); NMJs with CHRNE (39%) and COLQ (17%). Among MNDs, hereditary paraplegia, hereditary ataxias, and myotonic syndrome, the most frequently affected genes were SOD1 (34%), SPG11 (30%), SACS (36%), and CLCN1 (88%), respectively. In individuals with overlapping phenotypes, variants in DYSF (22%), RYR1 (8%), and LAMA2 (7%) were the most common genetic findings.

Conclusion:
A large cohort of individuals with NMDs provides valuable insights into mutational spectrum and disease patterns across populations. This study offers insights into the NMD profile within the Iranian population, which shows the impact of the high consanguinity rate on the prevalence of novel and inherited pathogenic variants. Understanding the genetic basis of NMDs can help patients, families, and healthcare providers manage these conditions more effectively.

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