Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders

Jong Hee Chae, Valeria Vasta, Anna Cho, Byung Chan Lim, Qing Zhang, So-Hee Eun, Si Houn Hahn

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Background: Neuromuscular disorders are a clinically, pathologically, and genetically heterogeneous group. Even for the experienced clinician, an accurate diagnosis is often challenging due to the complexity of these disorders. Here, we investigated the utility of next generation sequencing (NGS) in early diagnostic algorithms to improve the diagnosis for patients currently lacking precise molecular characterisation, particularly for hereditary myopathies. Methods: 43 patients presenting with early onset neuromuscular disorders from unknown genetic origin were tested by NGS for 579 nuclear genes associated with myopathy. Results: In 21 of the 43 patients, we identified the definite genetic causes (48.8%). Additionally, likely pathogenic variants were identified in seven cases and variants of uncertain significance (VUS) were suspected in four cases. In total, 19 novel and 15 known pathogenic variants in 17 genes were identified in 32 patients. Collagen VI related myopathy was the most prevalent type in our cohort. The utility of NGS was highlighted in three cases with congenital myasthenia syndrome, as early diagnosis is important for effective treatment. Conclusions: A targeted NGS can offer cost effective, safe and fairly rapid turnaround time, which can improve quality of care for patients with early onset myopathies and muscular dystrophies; in particular, collagen VI related myopathy and congenital myasthenia syndromes. Nevertheless, a substantial number of patients remained without molecular diagnosis in our cohort. This may be due to the intrinsic limitation of detection for some types of mutations by NGS or to the fact that other causative genes for neuromuscular disorders are yet to be identified.

Original languageEnglish
Pages (from-to)208-216
Number of pages9
JournalJournal of Medical Genetics
Volume52
Issue number3
DOIs
Publication statusPublished - 2015 Jan 1

Fingerprint

Muscular Diseases
Congenital Myasthenic Syndromes
Collagen
Genes
Inborn Genetic Diseases
Muscular Dystrophies
Quality of Health Care
Early Diagnosis
Costs and Cost Analysis
Mutation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders. / Chae, Jong Hee; Vasta, Valeria; Cho, Anna; Lim, Byung Chan; Zhang, Qing; Eun, So-Hee; Hahn, Si Houn.

In: Journal of Medical Genetics, Vol. 52, No. 3, 01.01.2015, p. 208-216.

Research output: Contribution to journalArticle

Chae, Jong Hee ; Vasta, Valeria ; Cho, Anna ; Lim, Byung Chan ; Zhang, Qing ; Eun, So-Hee ; Hahn, Si Houn. / Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders. In: Journal of Medical Genetics. 2015 ; Vol. 52, No. 3. pp. 208-216.
@article{715d30a32fc94f098a770f14ef445f47,
title = "Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders",
abstract = "Background: Neuromuscular disorders are a clinically, pathologically, and genetically heterogeneous group. Even for the experienced clinician, an accurate diagnosis is often challenging due to the complexity of these disorders. Here, we investigated the utility of next generation sequencing (NGS) in early diagnostic algorithms to improve the diagnosis for patients currently lacking precise molecular characterisation, particularly for hereditary myopathies. Methods: 43 patients presenting with early onset neuromuscular disorders from unknown genetic origin were tested by NGS for 579 nuclear genes associated with myopathy. Results: In 21 of the 43 patients, we identified the definite genetic causes (48.8{\%}). Additionally, likely pathogenic variants were identified in seven cases and variants of uncertain significance (VUS) were suspected in four cases. In total, 19 novel and 15 known pathogenic variants in 17 genes were identified in 32 patients. Collagen VI related myopathy was the most prevalent type in our cohort. The utility of NGS was highlighted in three cases with congenital myasthenia syndrome, as early diagnosis is important for effective treatment. Conclusions: A targeted NGS can offer cost effective, safe and fairly rapid turnaround time, which can improve quality of care for patients with early onset myopathies and muscular dystrophies; in particular, collagen VI related myopathy and congenital myasthenia syndromes. Nevertheless, a substantial number of patients remained without molecular diagnosis in our cohort. This may be due to the intrinsic limitation of detection for some types of mutations by NGS or to the fact that other causative genes for neuromuscular disorders are yet to be identified.",
author = "Chae, {Jong Hee} and Valeria Vasta and Anna Cho and Lim, {Byung Chan} and Qing Zhang and So-Hee Eun and Hahn, {Si Houn}",
year = "2015",
month = "1",
day = "1",
doi = "10.1136/jmedgenet-2014-102819",
language = "English",
volume = "52",
pages = "208--216",
journal = "Shock",
issn = "1073-2322",
publisher = "BMJ Publishing Group",
number = "3",

}

TY - JOUR

T1 - Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders

AU - Chae, Jong Hee

AU - Vasta, Valeria

AU - Cho, Anna

AU - Lim, Byung Chan

AU - Zhang, Qing

AU - Eun, So-Hee

AU - Hahn, Si Houn

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background: Neuromuscular disorders are a clinically, pathologically, and genetically heterogeneous group. Even for the experienced clinician, an accurate diagnosis is often challenging due to the complexity of these disorders. Here, we investigated the utility of next generation sequencing (NGS) in early diagnostic algorithms to improve the diagnosis for patients currently lacking precise molecular characterisation, particularly for hereditary myopathies. Methods: 43 patients presenting with early onset neuromuscular disorders from unknown genetic origin were tested by NGS for 579 nuclear genes associated with myopathy. Results: In 21 of the 43 patients, we identified the definite genetic causes (48.8%). Additionally, likely pathogenic variants were identified in seven cases and variants of uncertain significance (VUS) were suspected in four cases. In total, 19 novel and 15 known pathogenic variants in 17 genes were identified in 32 patients. Collagen VI related myopathy was the most prevalent type in our cohort. The utility of NGS was highlighted in three cases with congenital myasthenia syndrome, as early diagnosis is important for effective treatment. Conclusions: A targeted NGS can offer cost effective, safe and fairly rapid turnaround time, which can improve quality of care for patients with early onset myopathies and muscular dystrophies; in particular, collagen VI related myopathy and congenital myasthenia syndromes. Nevertheless, a substantial number of patients remained without molecular diagnosis in our cohort. This may be due to the intrinsic limitation of detection for some types of mutations by NGS or to the fact that other causative genes for neuromuscular disorders are yet to be identified.

AB - Background: Neuromuscular disorders are a clinically, pathologically, and genetically heterogeneous group. Even for the experienced clinician, an accurate diagnosis is often challenging due to the complexity of these disorders. Here, we investigated the utility of next generation sequencing (NGS) in early diagnostic algorithms to improve the diagnosis for patients currently lacking precise molecular characterisation, particularly for hereditary myopathies. Methods: 43 patients presenting with early onset neuromuscular disorders from unknown genetic origin were tested by NGS for 579 nuclear genes associated with myopathy. Results: In 21 of the 43 patients, we identified the definite genetic causes (48.8%). Additionally, likely pathogenic variants were identified in seven cases and variants of uncertain significance (VUS) were suspected in four cases. In total, 19 novel and 15 known pathogenic variants in 17 genes were identified in 32 patients. Collagen VI related myopathy was the most prevalent type in our cohort. The utility of NGS was highlighted in three cases with congenital myasthenia syndrome, as early diagnosis is important for effective treatment. Conclusions: A targeted NGS can offer cost effective, safe and fairly rapid turnaround time, which can improve quality of care for patients with early onset myopathies and muscular dystrophies; in particular, collagen VI related myopathy and congenital myasthenia syndromes. Nevertheless, a substantial number of patients remained without molecular diagnosis in our cohort. This may be due to the intrinsic limitation of detection for some types of mutations by NGS or to the fact that other causative genes for neuromuscular disorders are yet to be identified.

UR - http://www.scopus.com/inward/record.url?scp=84930686269&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930686269&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2014-102819

DO - 10.1136/jmedgenet-2014-102819

M3 - Article

VL - 52

SP - 208

EP - 216

JO - Shock

JF - Shock

SN - 1073-2322

IS - 3

ER -