Premium
Frequent genes in rare diseases: panel‐based next generation sequencing to disclose causal mutations in hereditary neuropathies
Author(s) -
Dohrn Maike F.,
Glöckle Nicola,
Mulahasanovic Lejla,
Heller Corina,
Mohr Julia,
Bauer Christine,
Riesch Erik,
Becker Andrea,
Battke Florian,
Hörtnagel Konstanze,
Hornemann Thorsten,
Suriyanarayanan Saranya,
Blankenburg Markus,
Schulz Jörg B.,
Claeys Kristl G.,
Gess Burkhard,
Katona Istvan,
Ferbert Andreas,
Vittore Debora,
Grimm Alexander,
Wolking Stefan,
Schöls Ludger,
Lerche Holger,
Korenke G. Christoph,
Fischer Dirk,
Schrank Bertold,
Kotzaeridou Urania,
Kurlemann Gerhard,
Dräger Bianca,
Schirmacher Anja,
Young Peter,
SchlotterWeigel Beate,
Biskup Saskia
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14217
Subject(s) - genetics , gene , mutation , biology , dna sequencing , computational biology
Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot‐Marie‐Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Of these, 54.4% showed an autosomal dominant, 33.9% an autosomal recessive, and 11.6% an X‐linked inheritance. The most frequently affected genes were PMP 22 (16.4%), GJB 1 (10.7%), MPZ , and SH 3 TC 2 (both 9.9%), and MFN 2 (8.3%). We further detected likely or known pathogenic variants in HINT 1, HSPB 1, NEFL , PRX , IGHMBP 2, NDRG 1, TTR , EGR 2, FIG 4, GDAP 1, LMNA , LRSAM 1, POLG , TRPV 4, AARS , BIC 2, DHTKD 1, FGD 4, HK 1, INF 2, KIF 5A, PDK 3, REEP 1, SBF 1, SBF 2, SCN 9A, and SPTLC 2 with a declining frequency. Thirty‐four novel variants were considered likely pathogenic not having previously been described in association with any disorder in the literature. In one patient, two homozygous mutations in HK 1 were detected in the multigene panel, but not by whole exome sequencing. A novel missense mutation in KIF 5A was considered pathogenic because of the highly compatible phenotype. In one patient, the plasma sphingolipid profile could functionally prove the pathogenicity of a mutation in SPTLC 2 . One pathogenic mutation in MPZ was identified after being previously missed by Sanger sequencing. We conclude that panel based next generation sequencing is a useful, time‐ and cost‐effective approach to assist clinicians in identifying the correct diagnosis and enable causative treatment considerations.