Muddling Through Muscle Genes – The Quest For Diagnosis In 50 Patients With Neuromuscular Disorders Using Whole Exome Sequencing.

Abstract

Introduction: Neuromuscular disorders (NMDs) comprise a group of heterogeneous genetic diseases with a broad spectrum of overlapping clinical presentations which makes diagnosis challenging. Notably, whole-exome sequencing (WES) as an efficient technology advances the genetic diagnosis of NMDs. We aimed to investigate the clinical utility of WES with integrated diagnostic approach in the diagnostic pathway of rare NMDs. Methodology: Chinese patients with paediatric onset hereditary NMDs without a genetic diagnosis who were referred to the Department of Paediatrics and Adolescent Medicine, University of Hong Kong between September 2016 and August 2018, were recruited. Clinical information on presenting history, physical examination, biochemical, radiological, electrophysiological and histopathological findings, were collected. WES was performed for all patients. Variant calling and data analysis were performed using an in-house bioinformatics pipeline. The 2018 version of the gene table with a list of 443 NMD-associated genes was used for the first-tier analysis. If negative, open exome analysis was followed. Results: Fifty subjects (30 male, 20 female) with pediatric-onset neuromuscular diseases with clinically overlapping phenotypic presentation of unknown genetic cause underwent the WES. WES identified 13 causative mutations in 50 subjects. The overall diagnostic yield for WES was 26 % (13/50). The causative pathogenic variants identified included ACTA1 (n = 2), POMT1, COL6A1 (n = 2), MTMR2, LMNA, SEPN1, DNM2, TGFB1, MPZ, IGHMBP2 and LAMA2. The diagnostic yield of individual subgroups were 15% (4/27 subjects) for congenital myopathy, 45% (5/11 subjects) for muscular dystrophy, 27% (3/11 subjects) for hereditary peripheral neuropathy. In addition, 1 subject was diagnosed with NMD mimic due to TGFB1 mutation. The mutation in TGFB1 causes skeletal dysplasia with neuromuscular presentation. Two subjects have variants of uncertain significance (VUSs) in TTN and SCN11A, due to incompatible phenotypes. Conclusions: Based on this cohort study, we propose that WES should be introduced in the early diagnostic pathway with the integrated diagnostic approach to shorten the diagnostic odyssey in patients with rare NMDs. The findings of WES should always be interpreted with respect to patient’s clinical presentation, and need to be correlated with neuromuscular investigation findings.