Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders

Gloria T. Haskell, Michael C. Adams, Zheng Fan, Krunal Amin, Roberto J.Guzman Badillo, Linran Zhou, Christopher Bizon, Nizar Chahin, Robert S. Greenwood, Laura V. Milko, Yael Shiloh-Malawsky, Kristy R. Crooks, Natasha Strande, Michael Tennison, Christian R. Tilley, Alicia Brandt, Kirk C. Wilhelmsen, Karen Weck, James P. Evans, Jonathan S. Berg

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Objective: To evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs). Methods: We performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup. Results: The overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis. Conclusions: Genome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

Original languageEnglish (US)
Article numbere212
JournalNeurology: Genetics
Volume4
Issue number1
DOIs
StatePublished - Feb 1 2018

Fingerprint

Exome
Genes
Genome
Phenotype
Workflow
Muscular Diseases
Routine Diagnostic Tests
Medical Records
Biopsy
Muscles

ASJC Scopus subject areas

  • Clinical Neurology
  • Genetics(clinical)

Cite this

Haskell, G. T., Adams, M. C., Fan, Z., Amin, K., Badillo, R. J. G., Zhou, L., ... Berg, J. S. (2018). Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders. Neurology: Genetics, 4(1), [e212]. https://doi.org/10.1212/NXG.0000000000000212

Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders. / Haskell, Gloria T.; Adams, Michael C.; Fan, Zheng; Amin, Krunal; Badillo, Roberto J.Guzman; Zhou, Linran; Bizon, Christopher; Chahin, Nizar; Greenwood, Robert S.; Milko, Laura V.; Shiloh-Malawsky, Yael; Crooks, Kristy R.; Strande, Natasha; Tennison, Michael; Tilley, Christian R.; Brandt, Alicia; Wilhelmsen, Kirk C.; Weck, Karen; Evans, James P.; Berg, Jonathan S.

In: Neurology: Genetics, Vol. 4, No. 1, e212, 01.02.2018.

Research output: Contribution to journalArticle

Haskell, GT, Adams, MC, Fan, Z, Amin, K, Badillo, RJG, Zhou, L, Bizon, C, Chahin, N, Greenwood, RS, Milko, LV, Shiloh-Malawsky, Y, Crooks, KR, Strande, N, Tennison, M, Tilley, CR, Brandt, A, Wilhelmsen, KC, Weck, K, Evans, JP & Berg, JS 2018, 'Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders', Neurology: Genetics, vol. 4, no. 1, e212. https://doi.org/10.1212/NXG.0000000000000212
Haskell, Gloria T. ; Adams, Michael C. ; Fan, Zheng ; Amin, Krunal ; Badillo, Roberto J.Guzman ; Zhou, Linran ; Bizon, Christopher ; Chahin, Nizar ; Greenwood, Robert S. ; Milko, Laura V. ; Shiloh-Malawsky, Yael ; Crooks, Kristy R. ; Strande, Natasha ; Tennison, Michael ; Tilley, Christian R. ; Brandt, Alicia ; Wilhelmsen, Kirk C. ; Weck, Karen ; Evans, James P. ; Berg, Jonathan S. / Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders. In: Neurology: Genetics. 2018 ; Vol. 4, No. 1.
@article{9d57c19a0bd8414b83e484ab54dcd8da,
title = "Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders",
abstract = "Objective: To evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs). Methods: We performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup. Results: The overall diagnostic yield of exome sequencing in our cohort was 12.9{\%}, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63{\%}) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis. Conclusions: Genome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.",
author = "Haskell, {Gloria T.} and Adams, {Michael C.} and Zheng Fan and Krunal Amin and Badillo, {Roberto J.Guzman} and Linran Zhou and Christopher Bizon and Nizar Chahin and Greenwood, {Robert S.} and Milko, {Laura V.} and Yael Shiloh-Malawsky and Crooks, {Kristy R.} and Natasha Strande and Michael Tennison and Tilley, {Christian R.} and Alicia Brandt and Wilhelmsen, {Kirk C.} and Karen Weck and Evans, {James P.} and Berg, {Jonathan S.}",
year = "2018",
month = "2",
day = "1",
doi = "10.1212/NXG.0000000000000212",
language = "English (US)",
volume = "4",
journal = "Neurology: Genetics",
issn = "2376-7839",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders

AU - Haskell, Gloria T.

AU - Adams, Michael C.

AU - Fan, Zheng

AU - Amin, Krunal

AU - Badillo, Roberto J.Guzman

AU - Zhou, Linran

AU - Bizon, Christopher

AU - Chahin, Nizar

AU - Greenwood, Robert S.

AU - Milko, Laura V.

AU - Shiloh-Malawsky, Yael

AU - Crooks, Kristy R.

AU - Strande, Natasha

AU - Tennison, Michael

AU - Tilley, Christian R.

AU - Brandt, Alicia

AU - Wilhelmsen, Kirk C.

AU - Weck, Karen

AU - Evans, James P.

AU - Berg, Jonathan S.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Objective: To evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs). Methods: We performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup. Results: The overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis. Conclusions: Genome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

AB - Objective: To evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs). Methods: We performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup. Results: The overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis. Conclusions: Genome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

UR - http://www.scopus.com/inward/record.url?scp=85048730190&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048730190&partnerID=8YFLogxK

U2 - 10.1212/NXG.0000000000000212

DO - 10.1212/NXG.0000000000000212

M3 - Article

AN - SCOPUS:85048730190

VL - 4

JO - Neurology: Genetics

JF - Neurology: Genetics

SN - 2376-7839

IS - 1

M1 - e212

ER -