Diagnostic value of whole‐exome sequencing in Chinese pediatric‐onset neuromuscular patients

Abstract

BackgroundNeuromuscular disorders (NMDs) comprise a group of heterogeneous genetic diseases with a broad spectrum of overlapping the clinical presentations that makes diagnosis challenging. Notably, the recent introduction of whole‐exome sequencing (WES) is introducing rapid changes on the genetic diagnosis of NMDs. We aimed to investigate the diagnostic value of WES for pediatric‐onset NMDs.MethodsWe applied integrated diagnostic approach and performed WES in 50 Chinese subjects (30 males, 20 females) with undiagnosed pediatric‐onset NMDs despite previous specific tests. The patients were categorized in four subgroups according to phenotyping and investigation findings. Variants on NMDs gene list and open exome analysis for those with initial negative findings were identified.ResultsWES identified causative variants in ACTA1 (n = 2), POMT1, COL6A1 (n = 2), MTMR2, LMNA, SELENON, DNM2, TGFB1, MPZ, IGHMBP2, and LAMA2 in 13 patients. Two subjects have variants of uncertain significance (VUSs) in TTN and SCN11A, unlikely to be pathogenic due to incompatible phenotypes. The mean interval time from symptom onset to genetic diagnosis was 10.4 years (range from 1 month to 33 years). The overall diagnostic yield of WES in our cohort was 26%. Open exome analysis was necessary to identify the pathogenic variant in TGFB1 that caused skeletal dysplasia with neuromuscular presentation.ConclusionOur study shows a clear role of WES in the pathway of integrated diagnostic approach to shorten the diagnostic odyssey in patients with rare NMDs.

Diagnostic yield of exome sequencing in myopathies: Experience of a Slovenian tertiary centre

“…They increased their diagnostic efficacy using neuromuscular gene panel to 75% and to 79% using WES. In recent study, WES analysis was conducted on 50 patients with undiagnosed paediatric‐onset neuromuscular diseases resulting with the overall diagnostic yield of 26% [ 22 ]. Diagnostic rate among patients with hereditary congenital myopathy was 17% and among patients with hereditary muscular dystrophy subgroup was 45%.…”

“…A growing body of literature has been investigating the benefits and the challenges of NGS based technology implementation in the standard clinical practice of patients with inherited myopathies [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. So far, however, fewer studies have been conducted on patients with unselected primary muscular disease, whereas reported diagnostic yield ranged between 16% and 36% [15][16][17][18][19].…”

“…There is a high variability in selection of NGS based diagnostic approaches for characterisation of patients with myopathies and the diagnostic yield obtained from the implementation of such methodologies varies significantly between studies [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Targeted gene panel sequencing approach was commonly used, but the selection of targeted genes differs greatly both in number and composition of genes [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22].…”

Two Novel Myelin Protein Zero Mutations in a Group of Chinese Patients

“…Previous studies have shown that the spectra and frequencies of MPZ mutations in Caucasian and Japanese cohorts are different (7). Several studies have reported Chinese patients with MPZ mutations, but it is currently unknown whether there are differences in the spectra of MPZ mutations between Chinese and other ethnicities (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Herein, we report the mutational spectrum and clinical features of six unrelated Chinese families with MPZ in our hospital over a 7 years period.…”

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“…Genomic DNA was extracted from ethylenediamine tetraacetic acid (EDTA) blood. Mutation analysis was performed by whole-exome sequencing and confirmed by Sanger sequencing (11). Compound heterozygous mutations of SELENON gene were identified in all the patients and confirmed by familial segregation analysis.…”