Three widespread founder mutations contribute to high incidence of X-linked juvenile retinoschisis in Finland.

X-linked juvenile retinoschisis (RS) is a recessively inherited disorder causing progressive vitreoretinal degeneration in males. The gene defective in retinoschisis, XLRS1, has recently been identified and characterised. This gene consists of six exons encoding a protein with a putative role in cell-cell adhesion and phospholipid binding. Juvenile retinoschisis has been actively studied in Finland over the past 30 years, with over 300 diagnosed RS patients. Based on genealogical studies, approximately 70% of the Finnish RS patients originate from Western Finland and 20% from Northern Finland. In this study, one third of the known Finnish RS patients were screened for mutations of the XLRS1 gene. Haplotype analysis, using nine microsatellite markers spanning 1 cM in Xp22.2, suggested the segregation of eight different mutations in these families. To identify mutations, the six exons were amplified by PCR and analysed by single strand conformation analysis, followed by direct sequencing of the PCR products. We identified seven distinct missense mutations, all in exons 4 and 6. The mutations in exon 4, 214G > A and 221G > T, are accountable for RS in Western Finland. A third mutation in exon 4, 325G > C, gives rise to RS in Northern Finland. These three founder mutations are the predominant cause of RS in Finland and their existence explains the high incidence of the disease. The identification of mutations common in genetically isolated populations, such as Finland, allows the diagnosis of patients with an atypical RS phenotype and enables nationwide carrier testing and improved genetic counselling.