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Dianna K H Wheaton, Kaylie D Webb-Jones, Sara J Bowne, Lori S Sullivan, Rui Chen, Stephen P Daiger, David G Birch; Complex Multi-Allelic Inherited Retinal Dystrophy: Multiple Genes Contributing Independently and Concurrently in Extended Families. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3135.
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© ARVO (1962-2015); The Authors (2016-present)
With recent availability of next-generation sequencing (NGS) it is becoming more common to pursue panel testing rather than targeted, sequential gene-by-gene testing. Herein, we describe the identification of multiple, concurrent disease-causing mutations contributing to retinal dystrophy in three relatively small families.
Family members underwent comprehensive visual function evaluations. An implied genetic inheritance pattern was assigned and updated as additional family members were tested. Family 1 (FAM1) and Family 2 (FAM2) were clinically diagnosed as dominant retinitis pigmentosa (adRP) with suspected non-penetrance (n.p.). Family 3 (FAM3) had an overall adRP pedigree, but the proband was phenotypically cone-rod dystrophy. Genetic analysis was performed by Sanger sequencing, and targeted retinal capture NGS to identify the underlying cause of disease.
Genetic testing of FAM1 (n=4 affected, 1 n.p.) identified a dominant RP1 mutation (c.2029C>T, p.Arg67Ter) that was present for 3 of the 4 affected individuals but absent in the proband and non-penetrant individual. NGS revealed the proband was a compound heterozygote for USH2A mutations (c.1256G>T, p. Cys419Phe / c.2299delG, p.Glu767Serfs*21). FAM2 genetic testing (n=3 affected, 1 n.p.) identified three different retinal dystrophy genes (PRPH2, PRPF8, USH2A) with disease-causing mutations. Affected FAM2 individuals each had a different genotype responsible for their retinal disease. Genetic testing for FAM3 (n=6 affected) identified a PRPH2 mutation (c.647C>T, p.Pro216Leu) tracking with disease in 5 of the 6 affected individuals. Additional testing determined the FAM3 proband harbored compound PRPH2 and CRX dominant mutations with CRX likely accounting for her cone-rod phenotype; her son harbored only the CRX mutation.
Using NGS we are discovering multiple genes contributing to the retinal dystrophy genotypes within a family. Families with noted examples of phenotypic variation or apparent non-penetrant individuals may offer a clue to suspect complex inheritance. Furthermore, this finding underscores that caution should be taken when attributing a single gene disease-causing mutation (or inheritance pattern) to a family as a whole.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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