Abstract
Purpose :
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.
Methods :
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.
Results :
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.
Conclusions :
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.