Whole Exome Sequencing (WES) for Rare Paediatric Neuromuscular Disorders in Hong Kong West Cluster

Abstract Description

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Authors (including presenting author) :

Tsang HYM(1)(2), Chiu ATG(1), Yu HCM(1), Fung LFJ(1), Liang M(1), Chung HYB*(1), Chan HSS*(1)

Affiliation :

(1) Department of Paediatrics & Adolescent Medicine, The University of Hong Kong (2) Department of Pathology, Hong Kong Children’s Hospital (TsangHYM is working in HKCH and studying part-time PhD in HKU. This abstract is part of her PhD study.)

Introduction :

Hereditary neuromuscular disorders (NMDs) are rare. They affect muscle and/or nerves with neonatal and childhood onset that could result in significant disability and higher mortality. Diagnosis of rare paediatric NMDs is challenging as they are clinically and genetically heterogeneous and have large gene involvement.

Objectives :

We aim to investigate the application of WES, as a research and diagnostic strategy, in our NMDs patients.

Methodology :

We recruited paediatrics-onset NMDs patients with clinical details and neuromuscular investigatory information. Most of them were tested negative with conventional genetic approach. WES and bioinformatics analysis were performed using our in-house pipeline. Rare variants were interrogated for pathogenicity based on the ACMG guideline. The overall interpretation was based on patients’ phenotypes and genetic results.

Result & Outcome :

Fifty patients (male=33, female=17) with median onset age at 1 year old were recruited. We identified disease-causing mutations in 12 cases, giving a diagnostic yield of 24% (12/50). These mutations were found in ACTA1, POMT1, COL6A1(n=2), MTMR2, LMNA, SEPN1, DNM2, TGFB1, MPZ, IGHMBP2 and LAMA2 gene. Two cases with variant of uncertain significance (VUS) were found in TTN and SCN11A respectively. NMDs patients can benefit from WES in three aspects. First, the genetic diagnosis can support clinical diagnosis. Two patients clinically suspected to have collagen VI-related myopathy is confirmed to have COL6A1 mutation. Second, WES helps the diagnosis of non-NMDs with neuromuscular presentation. The TGFB1 mutation is identified in one patient with Camurati-Engelmann disease, a skeletal condition often presented with muscular dystrophy features. Third, WES identified variant that affect the management. Although the VUS findings in TTN cannot explain the neuromuscular disease phenotype, its association with primary cardiomyopathy lead to recommendation of cardiac surveillance. The diagnostic yield here is consistent with reported literatures. WES is an effective and promising tool in our NMDs patients. With the current decreasing WES cost, comprehensive clinical approach with WES as the first-line diagnostic tool should be considered to facilitate an early genetic diagnosis and shorten the diagnostic odyssey. *This study is supported by HRMF.