Novel mutations and genomic rearrangement expand the molecular pathogenesis of X-linked idiopathic infantile nystagmus

Abstract

Purpose: Idiopathic Infantile nystagmus (IIN [MIM# 310700]) is one of the most common forms of infantile nystagmus that arises independently leading to low visual acuity scores. The inheritance patterns of IIN are heterogeneous with X-linked inheritance as the most frequent one (OMIM 31700). Up to date three X-linked loci have been identified, more specifically at Xp11.4-p11.3 (CASK), Xp22 (GPR143), and Xq26-q27 (FRMD7) respectively. FRMD7-related Infantile Nystagmus (FIN) represents 50% of cases with X-linked IN. Thus far 45 unique FRMD7 mutations have been reported in FIN, all of which are coding mutations apart from one partial gene deletion. Here, we investigated the role of FRMD7 and GPR143 mutations and copy number variations (CNV) in the molecular pathogenesis of Idiopathic Infantile Nystagmus (IIN) in fifty unrelated Belgian probands.

Methods: We set up a comprehensive molecular genetic workflow based on Sanger sequencing, targeted next generation sequencing (NGS) of FRMD7 (NM_194277.2) and GPR143 (NM_000273.2), and CNV analysis of FRMD7 and GPR143 using multiplex ligation-dependent probe amplification (MLPA).

Results: In twelve unrelated probands, ten unique FRMD7 changes were found, five of which are novel: frameshift mutation c.2036del p.(Leu679Argfs*8), missense mutations c.801C>A p.(Phe267Leu) and c.875T>C p.(Leu292Pro), splice site mutation c.497+5G>A, and one genomic rearrangement (1.29 Mb deletion) in a syndromic case. Additionally, five known mutations were found: c.70G>A p.(Gly24Arg), c.886G>C p.(Gly296Arg), c.910C>T p.(Arg303*), c.2036del p.(Leu679Argfs*8) and c.660del p.(Asn221Ilefs*11). The latter was found in four independent families. Haplotype reconstruction suggests a potential founder effect. In silico predictions and segregation testing of these mutations support their pathogenic effect. No GPR143 mutations or CNVs were found in the remainder of the patients.

Conclusions: Overall, genetic defects of FRMD7 were found in 12/50 (24%) probands, five of which are novel. We found, for the first time, a genomic rearrangement of FRMD7 in IIN, expanding its mutational spectrum. In addition haplotype analysis suggested a founder effect for c.660del. Our study generates a discovery cohort of IIN patients harboring either undetected non-coding mutations of FRMD7 or mutations in genes at known or novel loci sustaining the genetic heterogeneity of IIN.