Mutations in FRMD7, a Novel Gene, Cause X-Linked Congenital Idiopathic Nystagmus

Abstract

Purpose:: Nystagmus consists of rhythmic involuntary ocular oscillations resulting in significant loss of vision. Congenital Idiopathic Nystagmus (CIN) can be sporadic or hereditary, X-linked inheritance being the commonest. We identified 36 families and 42 singletons with CIN with the aim to identity the gene(s) causing CIN and to correlate the phenotype with the genotype.

Methods:: We ascertained the phenotype of 448 subjects from 36 families and 42 singletons with CIN. Detailed ophthalmological examination and eye movement recordings using eye link infrared pupil tracker was performed. Electrodiagnostic tests were done on at least one member from each family.Linkage analysis was done using polymorphic markers flanking the region Xq26-27, refining of potential genetic interval. This was followed by gene sequencing.

Results:: Linkage analysis narrowed down the potential genetic interval to a 3 mB region at Xq26-27. We identified 22 mutations in the FERM domain of the novel gene FRMD7 (Xq26.2) in 26 families with X-linked CIN. 7% of singletons had mutations in the gene.We compared the clinical features of CIN subjects with and without mutations in FRMD7. There was no significant difference in visual acuity between the two groups. The prevalence of strabismus (5%) and head posture (2%) was lower in the FRMD7 group compared to subjects without mutations in the gene (9% & 37%, respectively). 41% of the female obligate carriers were affected, two having subclinical nystagmus. Horizontal optokinetic nystagmus was abnormal in obligate carriers.

Conclusions:: Mutations in a newly detected gene FRMD7 causes CIN. Subjects with CIN due to mutations in FRMD7 have less prevalence of AHP and strabismus. This gene codes for a protein containing the FERM domain. Function of the gene is unknown. However protein with similar amino acid homology (FARP2) is associated with control of neurite outgrowth in the developing nervous system.

Keywords: nystagmus • genetics • eye movements