Abstract
Purpose Idiopathic Infantile Nystagmus (IIN [MIM# 310700]) is one of the commonest forms of infantile nystagmus characterized by bilateral uncontrollable eye movements that does not manifest until the child starts to fixate objects at the age of three months leading to low visual acuity scores. Genetically IIN is a heterogeneous disorder which is mostly inherited in an X-linked fashion. There are three known loci and two identified genes. Approximately 50% of families with X-linked IIN have been shown to be linked to mutations in the FERM domain-containing protein 7 (FRMD7) gene. Thus far 45 unique mutations have been reported in FRMD7 related patients with IIN. We investigate the role of FRMD7 mutations and copy number variations in Belgian cohort of 49 unrelated families with a clinical diagnosis of IIN. Methods Forty-nine families underwent detailed ophthalmological examinations and DNA extraction. We set up a comprehensive molecular genetic test based on Sanger sequencing, targeted next generation sequencing (NGS) and copy number variation (CNV) analysis. The reference sequence used was NM_194277.2. Results In eleven unrelated Belgian families with IIN, seven 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 CNV (1.4 Mb deletion). .Additionally, four known mutations were found: missense mutations c.70G>A p.(Gly24Arg) and c.886G>C p.(Gly296Arg), nonsense mutation c.910C>T p.(Arg303*); frameshift mutations c.2036del p.(Leu679Argfs*8) and c.660del p.(Asn221Ilefs*11) which were found in a three independent families. Haplotype reconstruction suggests a potential founder effect in Belgian IIN patients. Segregation testing of these mutations was performed and supports their pathogenic effect. Conclusion Overall, we found both coding FRMD7 mutations and a CNV in 11/49 Belgian families with IIN (22%) and expand the mutational spectrum of FRMD7 as a common cause of IIN. Finally, our study generates a discovery cohort of IIN patients harboring either undetected mutations in non-coding region of FRMD7 or in genes at known or novel loci sustaining the genetic heterogeneity of the disease. [PUBLICATION ABSTRACT]