July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
A missense variant in CACNA1F causes variable phenotype in female carriers and hemizygous males of three unrelated Jewish families of Russian origin
Author Affiliations & Notes
  • Adva Kimchi
    Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  • Vardiella Meiner
    Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  • Orly Elpeleg
    Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  • Michal Macarov
    Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  • Anat Blumenfeld
    Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  • Isabelle S Audo
    Institut de la Vision, Sorbonne Universités, UPMC Univ Paris 06, Paris, France
  • Christina Zeitz
    Institut de la Vision, Sorbonne Universités, UPMC Univ Paris 06, Paris, France
  • Hadas Mechoulam
    Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  • Eyal Banin
    Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  • Dror Sharon
    Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  • Claudia Yahalom
    Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  • Footnotes
    Commercial Relationships   Adva Kimchi, None; Vardiella Meiner, None; Orly Elpeleg, None; Michal Macarov, None; Anat Blumenfeld, None; Isabelle Audo, None; Christina Zeitz, None; Hadas Mechoulam, None; Eyal Banin, None; Dror Sharon, None; Claudia Yahalom, None
  • Footnotes
    Support  Israeli Ministry of Health Grant 3-11893; Fondation Voir et Entendre, Prix Dalloz for “La recherche en ophtalmologie” (CZ) and LABEX LIFESENSES [reference ANR-10-LABX-65] supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d’Avenir program [ANR-11-IDEX-0004-0].
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 5415. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Adva Kimchi, Vardiella Meiner, Orly Elpeleg, Michal Macarov, Anat Blumenfeld, Isabelle S Audo, Christina Zeitz, Hadas Mechoulam, Eyal Banin, Dror Sharon, Claudia Yahalom; A missense variant in CACNA1F causes variable phenotype in female carriers and hemizygous males of three unrelated Jewish families of Russian origin. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5415.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
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.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×