High diagnostic yield of targeted next‐generation sequencing panel as a first‐tier molecular test for the patients with myopathy or muscular dystrophy

• Published in: Annals of human genetics 2023-05, Vol.87 (3), p.104-114
• Main Authors: Çavdarlı, Büşranur, Köken, Özlem Yayici, Satılmış, Saide Betül Arslan, Bilen, Şule, Ardıçlı, Didem, Ceylan, Ahmet Cevdet, Gündüz, Cavidan Nur Semerci, Topaloğlu, Haluk
• Format: Article
• Language: English
• Subjects: Anoctamins - genetics; Diagnosis; Dolichyl-phosphate-mannose-protein mannosyltransferase; Duchenne's muscular dystrophy; Dystrophin; Etiology; Gene deletion; Genes; High-Throughput Nucleotide Sequencing; Humans; molecular diagnosis; Muscular Dystrophies, Limb-Girdle - diagnosis; Muscular dystrophy; Muscular Dystrophy, Duchenne - diagnosis; Muscular Dystrophy, Duchenne - genetics; Mutation; Myopathy; Neuromuscular diseases; Patients; Pentosyltransferases - genetics; Phenotype; Phenotypes
• ISSN: 0003-4800; 1469-1809
• DOI: 10.1111/ahg.12492

Muscular dystrophies are a heterogeneous group of neuromuscular disorders with a wide range of the clinical and genetic spectrum. Whole‐exome sequencing (WES) has been on the rise to become the usual method of choice for molecular diagnosis in patients presenting with muscular dystrophy or congenital or metabolic myopathy phenotype. Here, we used a panel with 47 genes including not only muscular dystrophy but also myopathy‐associated genes that had been used as a first‐tier approach. A total of 146 patients who were referred to our clinic with the prediagnosis of muscular dystrophy and/or myopathy were included in the study. Dystrophin gene deletion/duplication was ruled out on the patients with a preliminary diagnosis of Duchenne muscular dystrophy. In this study, the molecular etiology of 67 patients was proved with the gene panel with a diagnostic yield of 46%. Causal variants were identified in 23 genes including CAPN3(11), DYSF(9), DMD(8), SGCA(5), TTN(4), LAMA2(3), LMNA(3), SGCB(3), COL6A1(3), DES (2), CAV3(2), FKRP(2), FKTN(2), ANO5, COL6A2, CLCN1, GNE, POMGNT1, POMGNT2, POMT2, SYNE1, TCAP, and FLNC with 16 novel variants. There were 27 patients with uncertain molecular results including the ones who had a variant of uncertain significance, who had only one heterozygous variant for an autosomal recessive disease, and the ones who had two variants in different genes. Molecular diagnosis in muscular dystrophy is essential to plan clinical management and choosing treatment options. Also, the results will affect the reproduction options. Targeted next‐generation sequencing is a cost‐effective method that reduces the WES requirements with a significant diagnostic rate.