Mapping And Cloning Of New Disease-causing Gene In A Autosomal Dominant Optic Disc Pits Family

Purpose:To characterize the clinical phenotype of autosomal dominant inherited optic disc pits(ODP)with complex ocular involvements in a Chinese consanguineous family,and to determine the genetic basis for the family.Methods:Twelve affected and three unaffected individuals were recruited from a multigenerational Chinese consanguineous family.The family was clinically characterized by completely ophthalmologic examinations.Genome-wide scan was performed to identify the pathogenic region associated with autosomal dominant optic disc anomalies.After a likely pathogenic linkage region was found on Chromosome 14,refined mapping was performed in the kindred to further evaluate candidate region in the family.Simultaneously,the whole exome sequencing was carried out to find the disease causing gene.Results:Clinically,all affected individuals in this four generation family had bilateral involvement,presented with a very different impact on visual acuity inter and intra-individually ranged from 20/20 to 20/500.All of them showed a normal or smaller size pale optic nerve head with multiple cilioretinal arteries,lack of central retinal artery and vein trunk,prominent cupping and glial tissue overlying the optic disc,and chorioretinal pigmentary disturbance surrounded the disk.Peripapillary retinoschisis showed on OCT varied greatly in both location and severity,some of them even had focal retinal pigment epithelium(RPE)atrophy due to long-term and severe retinoschisis.Visual field in affected members demonstrated an obviously enlarged physiologic blind spot,some of them had a defect correlated with the retinal and RPE atrophy.Clinically,no more other ocular malformation was detected and IOP was normal.Genetically,we preliminarily assigned significant candidate region in Chromosome 14 q11.2-q22.3 by genome-wide scan.Subsequently,further fine mapping in candidate region identified the refined region in 14q12-q22.1 in the kindred.A maximum multi-point LOD score of 3.91 was reached at marker D14S275 in 14q26.2.But no candidate genes were detected by the whole exome sequencing.Conclusions:We presented a novel phenotype of autosomal dominant inheritance of cavitary optic disc anomalies and peripapillary retinoschisis in a multigenerational Chinese family.Simultaneously,a novel locus for adRS has been assigned to chromosomal region 14q12-q22.1 associated with this disease.