title: Novel FRMD7 Mutations and Genomic Rearrangement Expand the Molecular Pathogenesis of X-Linked Idiopathic Infantile Nystagmus.
abstract: OBJECTIVE
  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.
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium Department of Ophthalmology, King Abdul-Aziz University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors: Basamat
authors: B
authors: AlMoallem
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Miriam
authors: M
authors: Bauwens
authors: Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.
authors: Sophie
authors: S
authors: Walraedt
authors: Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.
authors: Patricia
authors: P
authors: Delbeke
authors: Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.
authors: Julie
authors: J
authors: De Zaeytijd
authors: Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.
authors: Philippe
authors: P
authors: Kestelyn
authors: Department of Ophthalmology, Queen Fabiola Children's University Hospital, Brussels, Belgium.
authors: Françoise
authors: F
authors: Meire
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Sandra
authors: S
authors: Janssens
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Caroline
authors: C
authors: van Cauwenbergh
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Hannah
authors: H
authors: Verdin
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Sally
authors: S
authors: Hooghe
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Prasoon
authors: P
authors: Kumar Thakur
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Frauke
authors: F
authors: Coppieters
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Kim
authors: K
authors: De Leeneer
authors: Center for Human Genetics, Leuven University Hospitals, Leuven, Belgium.
authors: Koenraad
authors: K
authors: Devriendt
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.
authors: Bart P
authors: BP
authors: Leroy
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Elfride
authors: E
authors: De Baere
mesh_terms: D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D001530:Belgium; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics*; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D060148:HapMap Project; D006801:Humans; D007223:Infant; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D020125:Mutation, Missense / Q000235:genetics; D020417:Nystagmus, Congenital / Q000175:diagnosis / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D003598:Cytoskeletal Proteins; D005136:Eye Proteins; C516168:FRMD7 protein, human; C095276:GPR143 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins
keywords: FRMD7 mutations; MLPA; genomic rearrangement; idiopathic infantile nystagmus; next generation sequencing