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Exome sequencing establishes a gelsolin mutation as the cause of inherited bulbar-onset neuropathy.

ABSTRACT: INTRODUCTION:Progressive bulbar motor neuropathy is primarily caused by bulbar-onset ALS. Hereditary amyloidosis type IV also presents with a bulbar neuropathy that mimics motor neuron disease. The disease is prevalent in Finland only and is not commonly included in the differential diagnosis of ALS. METHODS:We studied 18 members of a family in which some had bulbar motor neuropathy, and we performed exome sequencing. RESULTS:Five affected family members were found to have a D187Y substitution in the GSN gene known to cause hereditary amyloidosis type IV. CONCLUSIONS:This American family presented with progressive bulbar neuropathy due to a gelsolin mutation not found in Finland. Hereditary amyloidosis type IV presents with bulbar motor neuropathy and not with peripheral neuropathy as occurs with common forms of amyloidosis. This report demonstrates the power of exome sequencing to determine the cause of rare hereditary diseases with incomplete or atypical phenotypes. Muscle Nerve 56: 1001-1005, 2017.

SUBMITTER: Caress JB

PROVIDER: S-EPMC5494018 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Exome sequencing establishes a gelsolin mutation as the cause of inherited bulbar-onset neuropathy.

Caress James B JB Johnson Janel O JO Abramzon Yevgeniya A YA Hawkins Gregory A GA Gibbs J Raphael JR Sullivan Elizabeth A EA Chahal Chamanpreet S CS Traynor Bryan J BJ

Muscle & nerve 20170323 5

<h4>Introduction</h4>Progressive bulbar motor neuropathy is primarily caused by bulbar-onset ALS. Hereditary amyloidosis type IV also presents with a bulbar neuropathy that mimics motor neuron disease. The disease is prevalent in Finland only and is not commonly included in the differential diagnosis of ALS.<h4>Methods</h4>We studied 18 members of a family in which some had bulbar motor neuropathy, and we performed exome sequencing.<h4>Results</h4>Five affected family members were found to have ...[more]

PMID: 28039894

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Project description: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.

Dataset Information

Exome sequencing establishes a gelsolin mutation as the cause of inherited bulbar-onset neuropathy.

Publications

Exome sequencing establishes a gelsolin mutation as the cause of inherited bulbar-onset neuropathy.

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