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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 mostly monogenic but very heterogeneous and so far have been associated with mutations in over 250 genes (the full list of genes can be found at https://sph.uth.edu/retnet/sum-dis.htm#A-genes). Despite substantial progress in sequencing and new disease gene discovery, current strategies can genetically solve only about – 2/3rds of IRD cases. The remaining missing diagnoses are in part due to new, unidentified IRD genes or elusive mutations in the known genes. For example, a considerable proportion of missing genetic causality is due to copy number variations (CNVs) or deep intronic variants that affect splicing, which are not readily available from the standard output of targeted next generation sequencing (NGS) sequencing pipelines. To identify the new genetic causality of IRDs, we integrate the techniques of targeted NGS (Genetic Eye Disease (GEDi)) as well as whole-genome sequencing.
We analyze the sequence data to search for rare variants and CNVs in the known IRD genes or new IRD gene candidates. TO discover new disease genes, we conduct two strategies: 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.
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.