Biallelic Loss-of-Function Variants in BICD1 Are Associated with Peripheral Neuropathy and Hearing Loss.

Area of Science:

• Genetics
• Neuroscience
• Otolaryngology

Background:

• Hearing loss and peripheral neuropathy are complex conditions with overlapping genetic and phenotypic features.
• Investigating shared genetic etiologies is crucial for understanding these disorders.

Observation:

• A large Ashkenazi Jewish family presented with co-occurring hearing loss and peripheral neuropathy.
• Exome sequencing identified a homozygous frameshift variant (c.1683dup) in the BICD1 gene in affected individuals.
• This BICD1 variant segregated with the phenotype within the family.

Findings:

• No pathogenic variants were found in known genes associated with hearing loss or peripheral neuropathy.
• BICD1 RNA levels were modestly reduced in patient fibroblasts.
• Western blot analysis revealed a complete absence of BICD1 protein in fibroblasts from affected individuals, indicating loss-of-function.

Implications:

• Bi-allelic loss-of-function variants in BICD1 are associated with hearing loss and peripheral neuropathy.
• BICD1 may play a critical role in the development or maintenance of auditory and peripheral nervous systems.
• Further studies are needed to confirm BICD1 as a causative gene for these combined phenotypes.