title: Genetic analysis of 10 pedigrees with inherited retinal degeneration by exome sequencing and phenotype-genotype association.
abstract: Our purpose was to identify causative mutations and characterize the phenotype associated with the genotype in 10 unrelated families with autosomal recessive retinal degeneration. Ophthalmic evaluation and DNA isolation were carried out in 10 pedigrees with inherited retinal degenerations (IRD). Exomes of probands from eight pedigrees were captured using Nimblegen V2/V3 or Agilent V5+UTR kits, and sequencing was performed on Illumina HiSeq. TheDHDDSgene was screened for mutations in the remaining two pedigrees with Ashkenazi Jewish ancestry. Exome variants were filtered to detect candidate causal variants using exomeSuite software. Segregation and ethnicity-matched control sample analysis were performed by dideoxy sequencing. Retinal histology of a patient withDHDDSmutation was studied by microscopy. Genetic analysis identified six known mutations inABCA4(p.Gly1961Glu, p.Ala1773Val, c.5461-10T>C),RPE65(p.Tyr249Cys, p.Gly484Asp),PDE6B(p.Lys706Ter) andDHDDS(p.Lys42Glu) and ten novel potentially pathogenic variants inCERKL(p.Met323Val fsX20),RPE65(p.Phe252Ser, Thr454Leu fsX31),ARL6(p.Arg121His),USH2A(p.Gly3142Ter, p.Cys3294Trp),PDE6B(p.Gln652Ter), andDHDDS(p.Thr206Ala) genes. Among these, variants/mutations in two separate genes were observed to segregate with IRD in two pedigrees. Retinal histopathology of a patient with aDHDDSmutation showed severe degeneration of retinal layers with relative preservation of the retinal pigment epithelium. Analysis of exome variants in ten pedigrees revealed nine novel potential disease-causing variants and nine previously reported homozygous or compound heterozygous mutations in theCERKL,ABCA4, RPE65,ARL6, USH2A,PDE6B, andDHDDSgenes. Mutations that could be sufficient to cause pathology were observed in more than one gene in one pedigree.
authors.affiliation: Shiley Eye Institute, University of California San Diego, La Jolla, California.
authors.forename: Pooja
authors.initials: P
authors.lastname: Biswas
authors.affiliation: Ophthalmology, University of California San Francisco, San Francisco, California.
authors.forename: Jacque L
authors.initials: JL
authors.lastname: Duncan
authors.affiliation: Shiley Eye Institute, University of California San Diego, La Jolla, California.
authors.forename: Bruno
authors.initials: B
authors.lastname: Maranhao
authors.affiliation: King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
authors.forename: Igor
authors.initials: I
authors.lastname: Kozak
authors.affiliation: Ophthalmology & Visual Science, University of Michigan Kellogg Eye Center, Ann Arbor, Michigan.
authors.forename: Kari
authors.initials: K
authors.lastname: Branham
authors.affiliation: Genetics and Ophthalmology, Genelabor, Goiânia, Brazil.
authors.forename: Luis
authors.initials: L
authors.lastname: Gabriel
authors.affiliation: Shiley Eye Institute, University of California San Diego, La Jolla, California.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Lin
authors.affiliation: Shiley Eye Institute, University of California San Diego, La Jolla, California.
authors.forename: Giulio
authors.initials: G
authors.lastname: Barteselli
authors.affiliation: Shiley Eye Institute, University of California San Diego, La Jolla, California.
authors.forename: Mili
authors.initials: M
authors.lastname: Navani
authors.affiliation: Shiley Eye Institute, University of California San Diego, La Jolla, California.
authors.forename: John
authors.initials: J
authors.lastname: Suk
authors.affiliation: Shiley Eye Institute, University of California San Diego, La Jolla, California.
authors.forename: Michelle
authors.initials: M
authors.lastname: Parke
authors.affiliation: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon; and.
authors.forename: Catherine
authors.initials: C
authors.lastname: Schlechter
authors.affiliation: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon; and.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Weleber
authors.affiliation: Ophthalmology & Visual Science, University of Michigan Kellogg Eye Center, Ann Arbor, Michigan.
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.affiliation: Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Gislin
authors.initials: G
authors.lastname: Dagnelie
authors.affiliation: Shiley Eye Institute, University of California San Diego, La Jolla, California.
authors.forename: Pauline
authors.initials: P
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: S Amer
authors.initials: SA
authors.lastname: Riazuddin
authors.affiliation: Shiley Eye Institute, University of California San Diego, La Jolla, California; rayyagari@ucsd.edu.
authors.forename: Radha
authors.initials: R
authors.lastname: Ayyagari
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D019883:Alkyl and Aryl Transferases / Q000235:genetics; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D012162:Retinal Degeneration / Q000235:genetics*; D052245:Usher Syndromes / Q000235:genetics; D019745:cis-trans-Isomerases / Q000235:genetics; D000099178:Retinoid Isomerohydrolase
chemical_list: D020727:ADP-Ribosylation Factors; D018528:ATP-Binding Cassette Transporters; D019883:Alkyl and Aryl Transferases; D017853:Phosphotransferases (Alcohol Group Acceptor); D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C056475:ABCA4 protein, human; C051389:dehydrodolichyl diphosphate synthetase; C066324:ceramide kinase; C491435:ARL6 protein, human
keywords: IRD; exome sequencing; genetics; phenotype-genotype; retinal degeneration