title: Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing.
abstract: Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype-phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identified 41 missense sequence variants in the known IPN genes in our cohort of 110 index patients. Nine variants (8%), identified in the genes MFN2, GJB1, BSCL2, and SETX, are previously reported mutations and considered to be pathogenic in these families. Twelve novel variants (11%) in the genes NEFL, TRPV4, KIF1B, BICD2, and SETX are implicated in the disease but require further evidence of pathogenicity. The remaining 20 variants were confirmed as polymorphisms (not causing the disease) and are detailed here to help interpret sequence variants identified in other family studies. Validation using segregation, normal controls, and bioinformatics tools was valuable as supporting evidence for sequence variants implicated in disease. In addition, we identified one SETX sequence variant (c.7640T>C), previously reported as a putative mutation, which we have confirmed as a nonpathogenic rare polymorphism. This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well-defined cases remains important and will account for most positive results.
authors: Northcott Neuroscience Laboratory, ANZAC Research Institute Sydney, Australia.
authors: Alexander P
authors: AP
authors: Drew
authors: Molecular Medicine Laboratory, Concord Hospital Sydney, Australia.
authors: Danqing
authors: D
authors: Zhu
authors: Northcott Neuroscience Laboratory, ANZAC Research Institute Sydney, Australia.
authors: Aditi
authors: A
authors: Kidambi
authors: Northcott Neuroscience Laboratory, ANZAC Research Institute Sydney, Australia.
authors: Carolyn
authors: C
authors: Ly
authors: Department of Biomedical Science, Faculty of Medicine, University of Malaya 50603, Kuala Lumpur, Malaysia.
authors: Shelisa
authors: S
authors: Tey
authors: Northcott Neuroscience Laboratory, ANZAC Research Institute Sydney, Australia ; Sydney Medical School, University of Sydney Sydney, Australia.
authors: Megan H
authors: MH
authors: Brewer
authors: Department of Biomedical Science, Faculty of Medicine, University of Malaya 50603, Kuala Lumpur, Malaysia.
authors: Azlina
authors: A
authors: Ahmad-Annuar
authors: Northcott Neuroscience Laboratory, ANZAC Research Institute Sydney, Australia ; Molecular Medicine Laboratory, Concord Hospital Sydney, Australia ; Sydney Medical School, University of Sydney Sydney, Australia.
authors: Garth A
authors: GA
authors: Nicholson
authors: Northcott Neuroscience Laboratory, ANZAC Research Institute Sydney, Australia ; Molecular Medicine Laboratory, Concord Hospital Sydney, Australia ; Sydney Medical School, University of Sydney Sydney, Australia.
authors: Marina L
authors: ML
authors: Kennerson
keywords: Charcot-Marie-Tooth disease; genetic diagnosis; inherited peripheral neuropathy; whole-exome sequencing