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Session


Keywords: Visual systems; Clinical testing; Family linkage analysis; Genetic testing; Identification of disease genes

Authors:
S.P. Daiger 1,2; L.S. Sullivan 1; S.J. Bowne 1; E.L. Cadena 1; D. Koboldt 3; E.A. Pierce 4; D.G. Birch 5

Affiliations:
1) Human Genetics Center, School of Public Health, The Univ. of Texas Health Science Center, Houston, TX; 2) Ruiz Dept. of Ophthalmology and Visual Science, The Univ. of Texas Health Science Center, Houston, TX; 3) Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH; 4) Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Boston, MA; 5) Retina Foundation of the Southwest, Dallas, TX


Background. Inherited, degenerative retinal diseases (IRD’s) affect more than 1.5 million people worldwide and are a major cause of legal blindness and loss of vision in young adults. Currently, there are a number of registered clinical trials and approved drugs for treating IRD patients with known disease-causing genes and mutations. Thus identifying the underlying cause of disease is not only of benefit to patients and families, but is a prerequisite for treatment. Panel testing of known IRD genes using next-generation sequencing (NGS) detects the cause in from 60% to 80% of cases, depending on the population tested. Among the remaining cases we have identified several large, complex, disease-causing structural variants not readily detected by conventional NGS.
Results. Our research focuses on families with autosomal dominant retinitis pigmentosa (adRP) and related dominant retinopathies. To date we have identified the cause in approximately 80% of cases. Our goal is to find the causes in the remaining 20%. Methods include linkage mapping, retinal targeted-capture NGS, whole-exome and whole-genome NGS, quantitative-PCR and quantitative-NGS, and Linked-Read 10X Genomics Chromium™ sequencing. Among the unsolved adRP cases one family was found to have a balanced translocation of the q terminus arms of chromosomes 2 and 4 involving 35 Mb and 73 Mb respectively. The likely cause of disease in this family is dysregulation of the LRAT gene on chromosome 4. The family also reports an increased incidence of miscarriages. In a second family, with dominant macular degeneration, we found a 60 kb tandem duplication of the PRDM13 gene on chromosome 6q. The tandem copies of the PRDM13 gene appear to be intact with unaltered flanking regulatory sequences. The likely cause of disease in the family is overexpression of the PRDM13 gene. The family has clinical features of North Carolina Macular Dystrophy, with appearance of unique macular pits at birth, suggesting an in utero effect. Finally, we and other investigators have reported megabase deletions of the PRPF31 gene on chromosome 19q as another cause of adRP.
Conclusions. These findings suggest that a substantial fraction of the unsolved IRD cases have structural mutations, in known disease-causing genes, not easily detected by conventional NGS. Further, large structural variants may have additional consequences such as increased miscarriages.