An important focus of the lab’s work is the discovery of new genetic defects leading to different forms of inherited retinal degenerations (IRDs). These include nonsyndromic diseases such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Cone (CD) and Cone-rod dystrophies (CRD) and syndromic forms such as Usher Syndrome and cilliopathies (e.g. Joubert, Senior-Loken, Bardet-Biedl syndromes). These diseases are very heterogeneous and so far have been associated with mutations in approximately 200 genes (the full list of genes can be found at https://sph.uth.edu/retnet/disease.htm#17.105d). However, it has been estimated that mutations in known IRD genes account for only 50-60% of cases and therefore much effort is still needed to discover the remaining genetic defects. To identify the new IRD associated genes we integrate the techniques of whole-exome sequencing, copy number variation (CNV) analysis, linkage and homozygosity mapping using SNP arrays. For these analyses we select patients that have been previously excluded for mutations in known IRD genes by a targeted next generation sequencing and CGH array studies. We conduct two strategies of novel gene discovery: 1) family genetics and 2) cohort based study. In family genetics we analyze all available family members and look for rare, likely pathogenic genetic variants that segregate with the phenotype. Examples of such families are presented in Figure 1. In the cohort based studies we select patients of similar phenotype, for which we do not have available family members, and analyze them together as a group. Here we search for common rare, likely pathogenic variants between the affected individuals. At the moment we study three distinct cohorts: Usher type I, LCA and pericentral RP patients
Figure 1. Example pedigrees of families selected for whole-exome sequencing without mutations in known IRD disease genes. Probands (P) are indicated. JS, Joubert syndrome.