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.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Klein
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Middha
authors.affiliation: Department of Neurology, China-Japan Friendship Hospital, Beijing, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Duan
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Litchy
authors.affiliation: Department of Neurology, China-Japan Friendship Hospital, Beijing, China.
authors.forename: Weihong
authors.initials: W
authors.lastname: Gu
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: P James B
authors.initials: PJ
authors.lastname: Dyck
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Ralitza H
authors.initials: RH
authors.lastname: Gavrilova
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Smith
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Kocher
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dyck
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics*; D005260:Female; D005796:Genes / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D011115:Polyneuropathies / Q000175:diagnosis / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
keywords: NEUROGENETICS; NEUROPATHY