Frequent genes in rare diseases: panel‐based next generation sequencing to disclose causal mutations in hereditary neuropathies

摘要

Abstract 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.