A missense variant in CACNA1F causes variable phenotype in female carriers and hemizygous males of three unrelated Jewish families of Russian origin

Abstract

Purpose : Mutations in CACNA1F have been reported to cause X-linked congenital stationary night blindness (CSNB), Aland Island eye disease and cone-rod dystrophy (CRD). Phenotypic expression in females was previously reported in some families. We report here genetic and clinical analysis of three unrelated Jewish families of Russian origin that were referred to genetic counselling due to variable ophthalmic phenotypes including congenital nystagmus, CSNB, cone dystrophy (CD) and CRD.

Methods : The study adhered to the tenets of the declaration of Helsinki. Whole exome sequencing (WES) or Sanger sequencing were used to detect the disease-causing mutation in the three index cases. Complete ophthalmologic examination was performed including visual acuity (VA), refraction, color vision testing, slit-lamp examination, fundoscopy and electroretinography (ERG).

Results : WES and Sanger sequencing revealed a previously described missense mutation c.2225T>G; p.F742C in CACNA1F (NM_001256789.2) as the cause of disease in all three families. WES data showed a shared haplotype suggesting p.F742C is a founder mutation. We identified four affected males, most showing moderate non-progressive visual impairment, and six carrier females with normal to moderate decreased vision. Congenital nystagmus was found in all affected males and in 4/6 female carriers. Nyctalopia and myopia was a common finding in both males and females. ERG responses had atypical features for CSNB, with mild to moderate decreased response in most patients (cones and rods). Two patients had mainly photopic function affected. Based on the initial presentation, patients received the clinical diagnosis of CD, CRD or CNSB.

Conclusions : Our data suggests that p.F742C in CACNA1F is a possible founder mutation in Jewish families originating in Russia. This mutation causes a variable phenotype that was expressed in most female carriers. The variable expressivity of symptoms in female carriers supports the mechanism of differential X-inactivation. Our results highlight the importance and relevance of WES in the clinical setting, allowing fast and accurate genetic diagnosis when the clinical phenotype is unclear and in pedigrees in which X-linked inheritance is not the initial assumed inheritance pattern.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.