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

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 PMP22 (16.4%), GJB1 (10.7%), MPZ, and SH3TC2 (both 9.9%), and MFN2 (8.3%). We further detected likely or known pathogenic variants in HINT1, HSPB1, NEFL, PRX, IGHMBP2, NDRG1, TTR, EGR2, FIG4, GDAP1, LMNA, LRSAM1, POLG, TRPV4, AARS, BIC2, DHTKD1, FGD4, HK1, INF2, KIF5A, PDK3, REEP1, SBF1, SBF2, SCN9A, and SPTLC2 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 HK1 were detected in the multigene panel, but not by whole exome sequencing. A novel missense mutation in KIF5A 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 SPTLC2. 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.

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies

“…In the literature there are several targeted sequencing cohorts for NMDs, focusing on cases with motor neuron disorders; the number of the genes in the panels vary between 35 and 93, and the diagnostic yield between 20% and 35% (Antoniadi et al, 2015;Dohrn et al, 2017;Hoyer et al, 2014;Kruger et al, 2016;Lassuthova, et al, 2016;Lupo, et al, 2016). In an ALS cohort of 80 individuals, first tier analysis with ALS core genes (n = 39) provided a genetic diagnosis in 20 probands (25%).…”

Hereditäre Polyneuropathien

“…Deren Erfassung war mit der klassischen Sanger-Sequenzierung nur mit großem Aufwand zu erfassen, ist heute dank der Möglichkeiten des NGS jedoch deutlich einfacher geworden. Mit dieser Methode konnte ein nicht unerheblicher Teil von bislang ungeklärten CMT Fällen aufgeklärt werden, wobei die richtige Bewertung der großen Zahle gefundener Genvarianten eine neue Herausforderung darstellt [24], [29], [31], [32], [33], [34].…”

Rapidly progressive amyotrophic lateral sclerosis is associated with microglial reactivity and small heat shock protein expression in reactive astrocytes

“…HSPBs are a family of 11 highly conserved proteins that act as molecular chaperones and cytoskeleton stabilizers, exerting protective effects by reducing protein misfolding and promoting degradation of misfolded proteins . The role of HSPBs in neurodegenerative disorders is supported by studies showing that mutations in HSPB1, 3, 5 and 8 are associated with distal hereditary motor neuropathies and myofibrillar myopathies characterized by protein inclusions . In vitro , HSPB1, 5 and 8 prevent superoxide dismutase (SOD1) and TARDNA‐binding protein 43 (TDP‐43) aggregation by promoting degradation and solubility .…”