Eleven individuals of two unrelated consanguineous Bedouin families presented with severe early-onset retinitis pigmentosa (RP). All affected individuals exhibited severe disease with an onset in the second or third decade of life and severely reduced and delayed ERG responses. Combining 750k SNP array for all family members with whole exome sequencing of two affected family members, we identified in this kindred two different mutations in EYS (RP25): a deletion mutation encompassing 10 of the 43 exons and a p.W1817* nonsense mutation. Segregation analysis of both mutations demonstrated that all affected individuals were either homozygous for either one of the mutations, or compound heterozygous for both mutations. Both mutations are predicted to cause loss of function of the encoded protein and were not present in 200 ethnically-matched controls. Thus, we demonstrate pseudo-dominant heredity of RP in a consanguineous Bedouin clan caused by homozygosity and compound heterozygosity for two different EYS mutations: a nonsense mutation and a microdeletion. Our findings of two different mutations in the same gene in a single inbred kindred highlight the limitations of homozygosity mapping in disease-gene identification in inbred cohorts. Identification of the novel RP-causing mutations will facilitate early diagnosis, screening, and genetic counseling in the Bedouin population. Funding: the study was supported by an Israeli ministry of health research grant and Foundation Fighting Blidness USA (BR-GE-0214-0639).
|Journal||European Journal of Human Genetics|
|State||Published - Oct 2018|