APPLICATION OF NEXT GENERATION TECHNOLOGIES: EP.316 Diagnostic yield of targeted next-generation sequencing panels in muscular dystrophies

Abstract

Muscular dystrophies are a heterogeneous group of neuromuscular disorders with multigenic etiology. There are several subtypes of muscular dystrophy that have autosomal recessive, dominant or X-linked inheritance. Many myopathies or metabolic diseases can simulate muscle weakness observed in muscular dystrophy. Whole-exome sequencing (WES) has been the usual method of choice for molecular diagnosis in patients presenting with muscular dystrophy-myopathy phenotype. In terms of cost-effectivity, a panel with 47 genes including ANO5, CAPN3, CAV3, CLCN1, COL6A1, COL6A2, COL6A3, DAG1, DES, DMD, DNAJB6, DYSF, EMD, FHL1, FKRP, FKTN, FLNC, GAA, GMPPB, GNE, HNRNPDL, ISPD, LAMA2, LIMS2, LMNA, MYOT, PLEC, POMGNT1, POMGNT2, POMK, POMT1, POMT2, SEPN1, SGCA, SGCB, SGCD, SGCE, SGCG, SMCHD1, SYNE1, SYNE2, TCAP, TNPO3, TRAPPC11, TRIM32, TTN, VCP genes was designed as a first-tier genetic approach. This panel includes not only muscular dystrophy genes but also some metabolic disease and myopathy associated genes that causes proximal muscle weakness. This test was performed on 101 patients who were referred to our clinic due to muscular dystrophy. Dystrophin gene deletion/duplication analyses were also performed on the patients with a pre-diagnosis of Duchenne muscular dystrophy. Molecular etiology of 51 patients was solved with this panel which resulted as normal for 33 patients. There were 13 patients who had a variant of unknown clinical significance while a heterozygous pathogenic variant was detected in 9 patients for an autosomal recessive disease (CAPN3, SGCA, ANO5). Causal variants were identified in 22 genes including CAPN3(9), DYSF(6), TTN(4), SGCA(4), LAMA2(3), LMNA(3), SGCB(2), COL6A1(2), ANO5(2), DMD(2), CLCN1, DES, FLNC, FKRP, GNE, POMGNT1, POMGNT2, POMT1, POMT2, SYNE1, TCAP and CAV3. Four of the patients had compound heterozygous mutations (SGCA, ANO5, FKTN, DYSF), and also the molecular etiology of a patient, who had both POMT1 and POMT2 mutations, thought to be clarified by digenic inheritance. Molecular diagnosis in muscular dystrophy is essential to arrange the treatment options, reproductive choices, and predictions about prognosis. Targeted NGS is a cost-effective method that reduces the WES requirements by over 50% and provides a significant diagnostic rate.