Abstract
Purpose :
To determine the genetic etiology of a cohort of patients with ocular diseases who had undergone uninformative candidate gene analysis or clinical diagnostic panel testing and to test the yield of whole exome sequencing (WES)
Methods :
Subjects were from 12 families who research/clinical testing had failed to provide a genetic diagnosis. 3 families tested negative for candidate gene analysis in the CHM gene. The remaining 9 families had diagnoses of macular dystrophy, macular drusen, non-syndromic RP, dominant retinal dystrophy with detachment (RDD) and dominant cone rod dystrophy with cataract, deafness and learning disability. Testing with clinical approaches were negative.WES was performed by the BGI. Initial analysis compared WES to known disease ocular disease genes. Minor allele frequency (MAF) was assumed to be <0.1
Results :
Re-diagnoses
WES revealed the genetic etiology of 2/12 families and revised diagnosis: 1) heterozygous variant in RPE65 (p.D477G) replaced choroideremia (CHM) with chorioretinal-atrophy and 2) RP with Bardet-Biedl Syndrome (compound heterozygous variants in BBS1) in two brothers
Partially Solved
2/12 had heterozygous pathogenic variants in genes known to cause recessive conditions: 1) a single pathogenic mutation was revealed in ABCA4 indicating a putative diagnosis of Stargardt Macular Dystrophy, and 2) a pathogenic variant in PEX6 with presumed Heimler syndrome. Three heterozygous mutations were discovered in BBS genes (BBS5, IFT172, and WDPCP) in a patient thought to have CHM, but indicate a potential diagnosis of BBS
Novel Cases
8 remaining families analysis revealed potentially nove genes potentially involved in macular drusen in 2 families (LRP1, CPAMD8), and novel mutations in 9 genes in a family with RDD. Novel mutations were observed in EP400 and CSMD1 in a family with recessive macular dystrophy, while no variations were noted in one family with a recessive retinopathy, or a singleton with CHM. Analysis of a 3 generation family with a unique phenotype ( cone rod dystrophy, sensorineural hearing loss, and learning disability) indicated novel mutations in UBE2U, ANKRD36, and STUM
Conclusions :
Our intention is to develop process recommendations when transitioning patients to research studies. Personalized medicine includes careful individualized discussion with patients. Further studies are underway to determine the genes involved in each of the unknown or partially solved cases
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.