Clinical and molecular genetic analysis of early-onset myopathy with fatal cardiomyopathy: Novel biallelic M-line TTN mutation and review of the literature

Early-onset myopathy with fatal cardiomyopathy (EOMFC), also known as Salih myopathy (SALMY) 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. Titin (TTN) mutations that have been reported in congenital myopathies are associated with a variety of phenotypic spectrum of titinopathies, which are scattered along with the 364 exons of the gene. In this study, we report a consanguineous Moroccan female child aged 29 months who presented with congenital myopathy associated to dilated cardiomyopathy. Clinical Exome Sequencing identified a novel homozygous truncating mutation c.106541delA p.(Asp35514Valfs*32) in exon 361 of the TTN gene. Sanger sequencing confirmed the mutation in a homozygous state in the proband and in a heterozygous state in both of her parents. Clinical and molecular data of the proband were correlated with 15 patients reported in the literature for congenital myopathy associated to a heart defect or development of dilated cardiomyopathy with at least one mutant allele in the M-band titin protein as inclusion criteria. In conclusion, the application of NGS in rare genetic heterogeneous forms as EOMFC 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. •Early-onset myopathy with fatal cardiomyopathy (EOMFC) is a rare and heterogeneous form of recessive congenital titinopathies•A novel homozygous M-line TTN mutation identified in a Moroccan patient with EOMFC.•We contribute to expanding the clinical and mutational spectrum of this rare entity•This work highlights the importance of integrity of the last several exons of TTN gene and the implementation of NGS in genetic counseling.