A Novel Mutation in the FRMD7 Gene Causes Congenital Idiopathic Nystagmus

Abstract

Purpose: : To perform clinical characterization and determine the genetic basis of congenital X-linked Idiopathic Congenital Nystagmus (ICN) in one family.

Methods: : The study design is a clinical and family-based genetic study. Clinical and family histories were used to construct a pedigree of the ICN trait across 5 generations. Clinical exam including standard ophthalmic exam with dilated ophthalmoscopy and imaging were performed on the proband. DNA sequencing of FRMD7 gene was performed.

Results: : The proband is a female infant who has one affected maternal uncle and two affected maternal great-uncles. A maternal great-great grandfather, nowdeceased, was also affected. The affected child has characteristic clinical features of ICN including head bobbing, left-sided face tilt, and high amplitude, low-frequency, horizontal eye movements. Ophthalmic evaluation also revealed mild bilateral hyperopia. DNA sequencing identified a novel single base A>G substitution mutation in the 4+ position of the first intron of the FRMD7 gene. The IVS1+4 A>G mutation is a splice site mutation that destroys the splice donor site in intron 1. This mutation is predicted to cause abnormal gene splicing, either leading to an abnormal mRNA that is subject to nonsense-mediated decay or an abnormal protein.

Conclusions: : Our result identified novel mutation and broadens the spectrum of FRMD7 mutations in ICN, and further confirms the role of FRMD7 in the pathogenesis of ICN. The newly identified mutation may have the potential to cause ICN in hemizygous males, homozygous females, compound heterozygous females, or even in carrier females with substantial X-inactivation of the normal gene.

Keywords: nystagmus • genetics • gene screening