Abstract
Purpose:
Inherited retinal diseases are phenotypically and genetically heterogeneous. Patients with one clinical diagnosis may carry pathogenic mutations in disease genes that are not typically associated with that clinical diagnosis. An accurate molecular diagnosis can help to refine and improve the clinical diagnosis.
Methods:
We applied target capture next generation sequencing in a clinical diagnostic setting for the molecular diagnosis of 112 retinal disease patients, including 90 with retinitis pigmentosa (RP), 12 with Leber congenital amaurosis (LCA), and 10 with exudative vitreoretinopathy (FEVR) cases. For each case the coding exons and their 20 bp flanking regions of 207 eye disease genes were captured and sequenced. We first analyzed variants in canonical retinal disease for the corresponding patients, and then analyzed variants in the remaining eye disease related genes for the unsolved cases.
Results:
Pathogenic variants in canonical retinal disease genes were identified in 77% (69/90), 58% (7/12), and 30% (3/10) of RP, LCA, and FEVR cases respectively, suggesting high diagnostic yields. Among the remaining cases, pathogenic variants in non-canonical retinal disease genes were identified in 5 RP, 2 LCA, and 2 FEVR cases. For examples, one patient was suspected to have LCA but was found to carry compound heterozygous novel nonsense mutations in ALMS1. We later confirmed that this patient had hearing loss and mental retardation in addition to the blindness, which together resemble Alstrom syndrome. One patient tested negative for mutations in nonsyndromic RP genes was found to harbor a heterozygous reported mutation in GUCA1A, which has been associated with autosomal dominant cone dystrophy. Since this patient was 33 years old at the time of diagnosis, the disease may be at a late stage for clear distinction of the clinical differences. Another patient tested negative for mutations in FEVR genes was found to carry a hemizygous well known RS1 mutation. Since this patient had retinal detachment, his phenotype may fit the clinical diagnosis of retinoschisis.
Conclusions:
Our results highlighted the clinical and genetic heterogeneity of retinal diseases. To obtain a more accurate molecular diagnosis and increase the diagnostic yield, we need to sequence and analyze a larger set of related retinal disease genes.