Whole‐exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: Outcomes from a cohort of 50 families

Abstract

The inherited peripheral neuropathies (IPNs) are characterized by marked clinical and genetic heterogeneity and include relatively frequent presentations such as Charcot-Marie-Tooth disease and hereditary motor neuropathy, as well as more rare conditions where peripheral neuropathy is associated with additional features. There are over 250 genes known to cause IPN-related disorders but it is estimated that in approximately 50% of affected individuals a molecular diagnosis is not achieved. In this study, we examine the diagnostic utility of whole-exome sequencing (WES) in a cohort of 50 families with 1 or more affected individuals with a molecularly undiagnosed IPN with or without additional features. Pathogenic or likely pathogenic variants in genes known to cause IPN were identified in 24% (12/50) of the families. A further 22% (11/50) of families carried sequence variants in IPN genes in which the significance remains unclear. An additional 12% (6/50) of families had variants in novel IPN candidate genes, 3 of which have been published thus far as novel discoveries (KIF1A, TBCK, and MCM3AP). This study highlights the use of WES in the molecular diagnostic approach of highly heterogeneous disorders, such as IPNs, places it in context of other published neuropathy cohorts, while further highlighting associated benefits for discovery.

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

“…The diagnostic yield of NMD panel in pediatric and adolescent cases (32.5%) was higher than in adult cases (24%). This is compatible with two previous HMN cohorts providing data on the age of onset (Hartley et al, 2017;Schabhuttl et al, 2014), and emphasizes the importance of HTS diagnostics for non-5q-SMA in childhood. An early diagnosis for those cases may improve decision-making for symptomatic interventions, especially for such conditions as SMA with lower extremity predominance (SMALED2) in which no severe progression of weakness is expected (Neveling et al, 2013;Peeters et al, 2014).…”

“…WES is used as an alternative approach in HTS‐based diagnostics for motor neuron disorders. Thus, in a cohort with inherited peripheral neuropathy, 102 out of 354 (29%) individuals were diagnosed by WES (Hartley et al., ). When we resequenced our unsolved cases by WES or WGS, the diagnostic contribution of WES/WGS was much lower for cases unsolved by NMD panel analysis (11%) than by LMND panel (53%), which most likely reflects the larger known disease genes included in the NMD panel (Figures B and A).…”

“…Moreover, we regularly updated the NMD panel with newly identified genes. Since the discovery of novel disease genes is constantly decreasing (Boycott et al, 2017), the use of comprehensive NMD panels including all known NMD genes will provide a consistently increasing diagnostic performance in routine diagnostic testing.…”

Family with primary periodic paralysis and a mutation in MCM3AP, a gene implicated in mRNA transport

“…Patients in this family had a relatively late age of onset and attacks were associated with a relatively minor drop in K + . Previously described bi‐allelic MCM3AP mutations, likely loss‐of‐function, have been reported to result in Charcot–Marie–Tooth neuropathy with distal weakness and mild intellectual disability . However, pleiotropy (mutations in 1 gene causing multiple different traits) is not uncommon as mutations in 1,274 genes have been reported to result in 2 or more phenotypes in the Online Mendelian Inheritance in Man database .…”

Structural variations causing inherited peripheral neuropathies: A paradigm for understanding genomic organization, chromatin interactions, and gene dysregulation

“…Over 1,000 mutations in more than 80 genes have been associated with IPN subtypes (Timmerman, Strickland, & Zuchner, ). However, despite these discoveries, numerous whole‐exome sequencing studies to screen IPN cohorts have shown 18%–50% of cases (or higher) remain unsolved creating a significant burden for IPN diagnosis (Drew et al., ; Hartley et al., ; Lupo et al., ; Schabhuttl et al., ). In these cases where exome sequencing has failed to identify mutations in specific genes, it is likely a proportion of the neuropathy cases may be due to noncoding DNA or structural variation (SV) mutations.…”