Genomic study of a large family with complex neurological phenotype including hearing loss, imbalance and action tremor

Abstract

Neurological disorders are often associated with a variety of symptoms, which can result from the combined action of genetic variants. We conducted a whole-genome analysis of a previously unreported unique multigenerational Dutch-Canadian family with a complex phenotype presenting with a combination of hearing loss, balance issues or action tremor. Ten family members were available for genetic study. The hearing loss and balance problems are explained by a pathogenic p.P51S substitution in COCH, which is a known founder mutation in Dutch and Belgium families affected by non-syndromic progressive sensorineural hearing loss often accompanied by vestibular dysfunction. Notably, p.P51S did not co-segregate with action tremor in our and reported kindreds. In our family, all 5 patients with tremor were carriers of the extremely rare p.R247W substitution in MCM9 (minor allele frequency in European population is 0.00003), which belongs to the top 0.1% of deleterious variants in the human genome. The MCM9 locus has not been previously associated with action tremor and deserves further investigation in future functional and genetic studies of action tremor.

Keywords: COCH; Hearing loss; Imbalance; MCM9; Tremor.