M-line TTN Mutations in Salih Myopathy: Novel Biallelic Mutation and Review of the Literature

Abstract Background: Salih myopathy (SALMY), also known as early-onset myopathy with fatal cardiomyopathy (EOMFC) is a rare, heterogeneous, and severe form of titinopathies with autosomal recessive inherited neuromuscular disorders that affects both skeletal and cardiac muscles. It was previously identified only in the Arab population with unknown incidence. TTN mutations that have been reported in congenital myopathies are associated with a variety of phenotypic spectrum of titinopathies, which are scattered along the 364 exons of the gene. We report a Moroccan family with an affected patient diagnosed with Salih myopathy by next-generation sequencing (NGS) with a literature review of this rare entity.Methods: Genetic investigation by NGS was performed in a consanguineous Moroccan female child aged 29 months with congenital myopathy. Sanger sequencing confirmation was performed on the patient and both of her parents. Clinical and molecular data of the patient were correlated with 14 patients reported in the literature for congenital myopathy associated with a heart defect or development of dilated cardiomyopathy with at least one mutation in the M-band titin protein as inclusion criteria. Results: Bioinformatics analysis of Clinical Exome Sequencing (CES) data identified a novel homozygous truncating mutation c.106541delA p.(Asp35514Valfs*32) in exon 361 of the TTN gene. Sanger sequencing confirmed the mutation at a homozygous state in the proband and that both her parents are heterozygous carriers. Conclusions: Application of next-generation sequencing in rare genetic heterogeneous forms as SALMY provides more evidently an increasing proportion of congenital myopathies than currently recognized and expands the mutation spectrum of the TTN gene for better guiding the genetic diagnosis with adequate genetic counseling to the Moroccan families.