Phenotyping and Genotyping of Idiopathic Infantile Nystagmus

Background: Nystagmus can be a manifestation of ocular or systemic disorders. However, it may represent a separate disease entity by itself as in idiopathic infantile nystagmus (IIN). In 2004, Kerrison et al. localised the gene causing X-linked IIN to Xq26-27 (NYS1); however, the gene/genes causing IIN had not been identified. Aims and Objectives: The aims of this study were threefold. 1. To ascertain families and singletons (sporadic subjects) with IIN. 2. To further refine the locus NYS1 and to identify the gene causing X-linked IIN 3. To describe and compare the phenotype of subjects with IIN Methods: 39 families and 78 singletons with nystagmus were recruited and phenotyped. Genotyping with microsatellite markers were performed in the X-linked families to refine the genetic interval at Xq26-27. Gene sequencing was carried out by our collaborators (not by the author) at the Sanger Institute. The clinical features and eye movement recordings of 90 subjects with mutations in the FRMD7 gene were compared to 48 subjects with IIN not associated with mutations in this gene (non-FRMD7 group). Results: I: 149 familial subjects and 78 sporadic subjects with IIN were phenotyped. 121 subjects from 30 families were diagnosed to have X-linked IIN while 28 subjects from 9 families had other diagnosis such as albinism and aniridia. II: Genetic mapping in 16 families with X-linked IIN, refined the critical interval at Locus NYS1 (Xq26-17) to a 9mB region between markers DXS8072 and DXS8094 which contained about 80 genes. High throughput DNA sequencing was carried out at the Sanger Institute which led to the discovery of FRMD7, mutations in which is associated with X-linked IIN. III: The median visual acuity in subjects with a FRMD7 mutation was log MAR 0.301. The number of subjects with good stereopsis (Lang positive) was higher in the FRMD7 group (93.4%) compared to subjects in the non- FRMD7 group (78.4%). None of the subjects in the FRMD7 group had severe (>15˚) anomalous head posture (AHP) while 27% of subjects in the non-FRMD7 group had AHP more than 15˚. 52.17% of obligate female carriers of a FRMD7 mutation were clinically affected. Discussion: This study identified the first gene causing idiopathic infantile nystagmus. The phenotypic characteristics of these subjects will help in clinically identifying subjects with IIN due to mutations in FRMD7. In addition it has generated a stage for further research into the mechanisms behind ocular motor control.