Novel FRMD7 Mutations and Genomic Rearrangement Expand the Molecular Pathogenesis of X-Linked Idiopathic Infantile Nystagmus

Invest Ophthalmol Vis Sci. 2015 Feb 12;56(3):1701-10. doi: 10.1167/iovs.14-15938.


Purpose: Idiopathic infantile nystagmus (IIN; OMIM 31700) with X-linked inheritance is one of the most common forms of infantile nystagmus. Up to date, three X-linked loci have been identified, Xp11.4-p11.3 (calcium/calmodulin-dependent serine protein kinase [CASK]), Xp22 (GPR143), and Xq26-q27 (FRMD7), respectively. Here, we investigated the role of mutations and copy number variations (CNV) of FRMD7 and GPR143 in the molecular pathogenesis of IIN in 49 unrelated Belgian probands.

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

Results: In 11/49 probands, nine unique FRMD7 changes were found, five of which are novel: frameshift mutation c.2036del, missense mutations c.801C>A and c.875T>C, splice-site mutation c.497+5G>A, and one genomic rearrangement (1.29 Mb deletion) in a syndromic case. Additionally, four known mutations were found: c.70G>A, c.886G>C, c.910C>T, and c.660del. The latter was found in three independent families. In silico predictions and segregation testing of the novel mutations support their pathogenic effect. No GPR143 mutations or CNVs were found in the remainder of the probands (38/49).

Conclusions: Overall, genetic defects of FRMD7 were found in 11/49 (22.4%) probands, including the first reported genomic rearrangement of FRMD7 in IIN, expanding its mutational spectrum. Finally, we generate a discovery cohort of IIN patients potentially harboring either hidden a variation of FRMD7 or mutations in genes at known or novel loci sustaining the genetic heterogeneity of IIN.

Keywords: FRMD7 mutations; MLPA; genomic rearrangement; idiopathic infantile nystagmus; next generation sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged, 80 and over
  • Belgium
  • Child
  • Child, Preschool
  • Cohort Studies
  • Comparative Genomic Hybridization
  • Cytoskeletal Proteins / genetics*
  • DNA Mutational Analysis*
  • Eye Proteins / genetics
  • Female
  • Gene Rearrangement / genetics*
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease / genetics
  • Genetic Testing
  • HapMap Project
  • Humans
  • Infant
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Proteins / genetics*
  • Middle Aged
  • Multiplex Polymerase Chain Reaction
  • Mutation, Missense / genetics
  • Nystagmus, Congenital / diagnosis
  • Nystagmus, Congenital / genetics*
  • Sequence Analysis, DNA


  • Cytoskeletal Proteins
  • Eye Proteins
  • FRMD7 protein, human
  • GPR143 protein, human
  • Membrane Glycoproteins
  • Membrane Proteins

Supplementary concepts

  • Nystagmus 1, congenital, X- linked