Taylor & Francis Group
Browse
iopg_a_1681008_sm6884.pdf (304.81 kB)

An Ashkenazi Jewish founder mutation in CACNA1F causes retinal phenotype in both hemizygous males and heterozygous female carriers

Download (304.81 kB)
journal contribution
posted on 2019-10-25, 13:59 authored by Adva Kimchi, Vardiella Meiner, Shira Silverstein, Michal Macarov, Hagar Mor-Shaked, Anat Blumenfeld, Isabelle Audo, Christina Zeitz, Hadas Mechoulam, Eyal Banin, Dror Sharon, Claudia Yahalom

Background: Mutations in CACNA1F have been mainly associated with X-linked incomplete congenital stationary night blindness (icCSNB). Variable phenotypic expression in females was reported in some families. We report here three non-related Ashkenazi Jewish families originating in Eastern Europe, that included males and a many affected females, initially diagnosed with variable retinal phenotypes.

Materials and Methods: Whole exome sequencing (WES), Sanger sequencing and microsatellite haplotyping were used for genetic analysis. Complete ophthalmologic examination was performed including visual acuity, refraction, colour vision, slit-lamp, fundoscopy and electroretinography (ERG).

Results: We identified four affected males, showing moderate visual impairment, and seven female carriers, six of them presenting mild to moderate visual impairment. Infantile nystagmus was found in all affected males and in 5/7 females. Nyctalopia and myopia were common in both males and females. Initial clinical differential diagnosis included cone-dystrophy, cone-rod dystrophy, cone-dystrophy with supernormal rod response or CSNB based on ERG results. WES and Sanger sequencing revealed a previously described missense mutation c.2225T>G; p.(F742C) in CACNA1F (NM_001256789.2) in all three families, encompassed by a shared haplotype

Conclusions: Our data suggests that p.(F742C) in CACNA1F is an X-linked founder mutation in Ashkenazi Jews originating in Eastern Europe. This mutation causes a mild-to-moderate icCSNB phenotype, expressed in most female carriers. A targeted test for this variant in suspected patients may initiate diagnostic analysis. Our results highlight the relevance of WES in the clinic, allowing fast and accurate diagnosis for unclear and variable clinical phenotype and in pedigrees with multiple possible inheritance patterns.

Funding

This work was supported by the Israeli Ministry of Health [3-11893].

History

Usage metrics

    Ophthalmic Genetics

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC