A Novel Splice-Site Variant in CACNA1F Causes a Phenotype Synonymous with Åland Island Eye Disease and Incomplete Congenital Stationary Night Blindness.

Usman Mahmood,Igor Kozak,Mariya Moosajee,Cécile Méjécase,Syed M A Ali

doi:10.3390/genes12020171

Abstract

Background: CACNA1F-related disorders encompass progressive and non-progressive disorders, including Åland island eye disease and incomplete congenital stationary night blindness. These two X-linked disorders are characterized by nystagmus, color vision defect, myopia, and electroretinography (ERG) abnormalities. Ocular hypopigmentation and iris transillumination are reported only in patients with Åland island eye disease. Around 260 variants were reported to be associated with these two non-progressive disorders, with 19 specific to Åland island eye disease and 14 associated with both Åland island eye disease and incomplete congenital stationary night blindness. CACNA1F variants spread on the gene and further analysis are needed to reveal phenotype-genotype correlation. Case Report: A complete ocular exam and genetic testing were performed on a 13-year-old boy. A novel splice-site variant, c.4294-11C>G in intron 36 in CACNA1F, was identified at hemizygous state in the patient and at heterozygous state in his asymptomatic mother and explained the phenotype synonymous with Åland island eye disease and incomplete congenital stationary night blindness observed in the patient. Conclusion: We present a novel variant in the CACNA1F gene causing phenotypic and electrophysiologic findings indistinguishable from those of AIED/CSNB2A disease. This finding further expands the mutational spectrum and our knowledge of CACNA1F-related disease.

Highlights

Åland island eye disease (AIED; OMIM #300600), known as Forsius-Eriksson type ocular albinism, is an X-linked disorder first described in Norwegian descendants on theÅland Islands in the Sea of Bothnia [1]
The AIED gene locus has been localized to the pericentromeric region of the Xp11.23 chromosome, Xp11.23; shared with incomplete congenital stationary night blindness (CSNB2A, OMIM #300071) [8]
CSNB2A is a non-progressive condition characterized by nyctalopia, myopia, nystagmus, strabismus, and a negative ERG

Summary

Introduction

Åland island eye disease (AIED; OMIM #300600), known as Forsius-Eriksson type ocular albinism, is an X-linked disorder first described in Norwegian descendants on the. The AIED gene locus has been localized to the pericentromeric region of the Xp11.23 chromosome, Xp11.23; shared with incomplete congenital stationary night blindness (CSNB2A, OMIM #300071) [8]. CSNB2A is a non-progressive condition characterized by nyctalopia, myopia, nystagmus, strabismus, and a negative ERG Both AIED and CSNB2A result from variants in the calcium channel, voltage-dependent, α1F-subunit gene, CACNA1F (MIM 300110) [9], and have been suggested to be indistinct with genetic or environmental modifiers influencing the phenotypic variation. The following clinical features overlap between AIED and CSNB2A: decreased visual acuity, nystagmus, astigmatism, defective dark adaptation, and ERG abnormalities in both photopic and scotopic functions. In the CACNA1F gene at an evolutionarily highly conserved position that is predicted to be pathogenic by all applied in silico algorithms

Case Description

Discussion

CACNA1F