Application of whole exome sequencing in undiagnosed inherited polyneuropathies

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30 Citations (Scopus)

Abstract

Background: Inherited polyneuropathies often go undiagnosed. We investigated whole exome sequencing (WES) in utility to identify the genetic causes of diverse forms of inherited polyneuropathies without genetic diagnosis. Methods: WES was applied to 24 cases from 15 kindreds. These kindreds had earlier unsuccessful candidate gene testing and five probands were initially thought to have acquired neuropathy. We assessed the efficacy of WES in screening 74 known neuropathy genes and 5195 reported pathogenic mutations for hereditary motor and sensory neuropathy, distal hereditary motor neuropathy, hereditary sensory and autonomic neuropathy, complicated hereditary spastic paraplegia, and select hereditary metabolic neuropathies. Results: Pathogenic mutations were identified in five kindreds: (1) ATL1-p. Val253Ile; (2) LITAF-p. Gly112Ser; (3) MFN2-p. Arg94Gln; (4) GARS-p. Ile334Phe; and (5) BSCL2-p. Ser 90Leu. Complexities in establishing inheritance, difficulties in selecting candidate genes and high cost of gene testing all hindered earlier gene discoveries. WES expanded the phenotypic spectrum of the identified known mutations. Possible causal mutations in known genes (SPTLC1, DCTN1, REEP1) were identified in three kindreds. In the remaining seven kindreds, multiple rare or novel variants were identified in novel genes not previously linked with neuropathy. Our results demonstrate an average sequencing depth of 140×, ≥98% coverage and ≥10× sequencing depth for 93% (range 89%-96%) of the diverse neuropathy genes and their known mutations. Conclusions: Diverse inherited neuropathy patients without genetic discovery by candidate gene testing have a favourable probability of receiving a genetic diagnosis by WES. Frequently, atypical phenotypes account for earlier failed candidate approaches, and WES is demonstrated to expand the clinical spectrum of known pathogenic mutations.

Original languageEnglish (US)
JournalJournal of Neurology, Neurosurgery and Psychiatry
DOIs
StateAccepted/In press - Mar 6 2014

Fingerprint

Exome
Polyneuropathies
Mutation
Genes
Genetic Association Studies
Hereditary Sensory and Autonomic Neuropathies
Hereditary Sensory and Motor Neuropathy
Hereditary Spastic Paraplegia
Sequencing
Gene
Phenotype
Costs and Cost Analysis

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Surgery
  • Psychiatry and Mental health
  • Clinical Neurology

Cite this

@article{8af20327a3ad4649a02ae18090d518dd,
title = "Application of whole exome sequencing in undiagnosed inherited polyneuropathies",
abstract = "Background: Inherited polyneuropathies often go undiagnosed. We investigated whole exome sequencing (WES) in utility to identify the genetic causes of diverse forms of inherited polyneuropathies without genetic diagnosis. Methods: WES was applied to 24 cases from 15 kindreds. These kindreds had earlier unsuccessful candidate gene testing and five probands were initially thought to have acquired neuropathy. We assessed the efficacy of WES in screening 74 known neuropathy genes and 5195 reported pathogenic mutations for hereditary motor and sensory neuropathy, distal hereditary motor neuropathy, hereditary sensory and autonomic neuropathy, complicated hereditary spastic paraplegia, and select hereditary metabolic neuropathies. Results: Pathogenic mutations were identified in five kindreds: (1) ATL1-p. Val253Ile; (2) LITAF-p. Gly112Ser; (3) MFN2-p. Arg94Gln; (4) GARS-p. Ile334Phe; and (5) BSCL2-p. Ser 90Leu. Complexities in establishing inheritance, difficulties in selecting candidate genes and high cost of gene testing all hindered earlier gene discoveries. WES expanded the phenotypic spectrum of the identified known mutations. Possible causal mutations in known genes (SPTLC1, DCTN1, REEP1) were identified in three kindreds. In the remaining seven kindreds, multiple rare or novel variants were identified in novel genes not previously linked with neuropathy. Our results demonstrate an average sequencing depth of 140×, ≥98{\%} coverage and ≥10× sequencing depth for 93{\%} (range 89{\%}-96{\%}) of the diverse neuropathy genes and their known mutations. Conclusions: Diverse inherited neuropathy patients without genetic discovery by candidate gene testing have a favourable probability of receiving a genetic diagnosis by WES. Frequently, atypical phenotypes account for earlier failed candidate approaches, and WES is demonstrated to expand the clinical spectrum of known pathogenic mutations.",
author = "Klein, {Christopher Jon} and Sumit Middha and Xiaohui Duan and Yanhong Wu and Litchy, {William J} and Weihong Gu and Dyck, {P. James B} and Gavrilova, {Ralitza M} and Smith, {David I} and Jean-Pierre Kocher and Dyck, {Peter J}",
year = "2014",
month = "3",
day = "6",
doi = "10.1136/jnnp-2013-306740",
language = "English (US)",
journal = "Journal of Neurology, Neurosurgery and Psychiatry",
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TY - JOUR

T1 - Application of whole exome sequencing in undiagnosed inherited polyneuropathies

AU - Klein, Christopher Jon

AU - Middha, Sumit

AU - Duan, Xiaohui

AU - Wu, Yanhong

AU - Litchy, William J

AU - Gu, Weihong

AU - Dyck, P. James B

AU - Gavrilova, Ralitza M

AU - Smith, David I

AU - Kocher, Jean-Pierre

AU - Dyck, Peter J

PY - 2014/3/6

Y1 - 2014/3/6

N2 - Background: Inherited polyneuropathies often go undiagnosed. We investigated whole exome sequencing (WES) in utility to identify the genetic causes of diverse forms of inherited polyneuropathies without genetic diagnosis. Methods: WES was applied to 24 cases from 15 kindreds. These kindreds had earlier unsuccessful candidate gene testing and five probands were initially thought to have acquired neuropathy. We assessed the efficacy of WES in screening 74 known neuropathy genes and 5195 reported pathogenic mutations for hereditary motor and sensory neuropathy, distal hereditary motor neuropathy, hereditary sensory and autonomic neuropathy, complicated hereditary spastic paraplegia, and select hereditary metabolic neuropathies. Results: Pathogenic mutations were identified in five kindreds: (1) ATL1-p. Val253Ile; (2) LITAF-p. Gly112Ser; (3) MFN2-p. Arg94Gln; (4) GARS-p. Ile334Phe; and (5) BSCL2-p. Ser 90Leu. Complexities in establishing inheritance, difficulties in selecting candidate genes and high cost of gene testing all hindered earlier gene discoveries. WES expanded the phenotypic spectrum of the identified known mutations. Possible causal mutations in known genes (SPTLC1, DCTN1, REEP1) were identified in three kindreds. In the remaining seven kindreds, multiple rare or novel variants were identified in novel genes not previously linked with neuropathy. Our results demonstrate an average sequencing depth of 140×, ≥98% coverage and ≥10× sequencing depth for 93% (range 89%-96%) of the diverse neuropathy genes and their known mutations. Conclusions: Diverse inherited neuropathy patients without genetic discovery by candidate gene testing have a favourable probability of receiving a genetic diagnosis by WES. Frequently, atypical phenotypes account for earlier failed candidate approaches, and WES is demonstrated to expand the clinical spectrum of known pathogenic mutations.

AB - Background: Inherited polyneuropathies often go undiagnosed. We investigated whole exome sequencing (WES) in utility to identify the genetic causes of diverse forms of inherited polyneuropathies without genetic diagnosis. Methods: WES was applied to 24 cases from 15 kindreds. These kindreds had earlier unsuccessful candidate gene testing and five probands were initially thought to have acquired neuropathy. We assessed the efficacy of WES in screening 74 known neuropathy genes and 5195 reported pathogenic mutations for hereditary motor and sensory neuropathy, distal hereditary motor neuropathy, hereditary sensory and autonomic neuropathy, complicated hereditary spastic paraplegia, and select hereditary metabolic neuropathies. Results: Pathogenic mutations were identified in five kindreds: (1) ATL1-p. Val253Ile; (2) LITAF-p. Gly112Ser; (3) MFN2-p. Arg94Gln; (4) GARS-p. Ile334Phe; and (5) BSCL2-p. Ser 90Leu. Complexities in establishing inheritance, difficulties in selecting candidate genes and high cost of gene testing all hindered earlier gene discoveries. WES expanded the phenotypic spectrum of the identified known mutations. Possible causal mutations in known genes (SPTLC1, DCTN1, REEP1) were identified in three kindreds. In the remaining seven kindreds, multiple rare or novel variants were identified in novel genes not previously linked with neuropathy. Our results demonstrate an average sequencing depth of 140×, ≥98% coverage and ≥10× sequencing depth for 93% (range 89%-96%) of the diverse neuropathy genes and their known mutations. Conclusions: Diverse inherited neuropathy patients without genetic discovery by candidate gene testing have a favourable probability of receiving a genetic diagnosis by WES. Frequently, atypical phenotypes account for earlier failed candidate approaches, and WES is demonstrated to expand the clinical spectrum of known pathogenic mutations.

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U2 - 10.1136/jnnp-2013-306740

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