title: Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements.
abstract: Retinitis pigmentosa (RP) is a devastating form of retinal degeneration, with significant social and professional consequences. Molecular genetic information is invaluable for an accurate clinical diagnosis of RP due to its high genetic and clinical heterogeneity. Using a gene capture panel that covers 163 of the currently known retinal disease genes, including 48 RP genes, we performed a comprehensive molecular screening in a collection of 123 RP unsettled probands from a wide variety of ethnic backgrounds, including 113 unrelated simplex and 10 autosomal recessive RP (arRP) cases. As a result, 61 mutations were identified in 45 probands, including 38 novel pathogenic alleles. Interestingly, we observed that phenotype and genotype were not in full agreement in 21 probands. Among them, eight probands were clinically reassessed, resulting in refinement of clinical diagnoses for six of these patients. Finally, recessive mutations in CLN3 were identified in five retinal degeneration patients, including four RP probands and one cone-rod dystrophy patient, suggesting that CLN3 is a novel non-syndromic retinal disease gene. Collectively, our results underscore that, due to the high molecular and clinical heterogeneity of RP, comprehensive screening of all retinal disease genes is effective in identifying novel pathogenic mutations and provides an opportunity to discover new genotype-phenotype correlations. Information gained from this genetic screening will directly aid in patient diagnosis, prognosis, and treatment, as well as allowing appropriate family planning and counseling.
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA, fengw@bcm.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Han-Fang
authors.initials: HF
authors.lastname: Tuan
authors.forename: Duy H
authors.initials: DH
authors.lastname: Nguyen
authors.forename: Vincent
authors.initials: V
authors.lastname: Sun
authors.forename: Vafa
authors.initials: V
authors.lastname: Keser
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Bowne
authors.forename: Lori S
authors.initials: LS
authors.lastname: Sullivan
authors.forename: Hongrong
authors.initials: H
authors.lastname: Luo
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Zaneveld
authors.forename: Jason S
authors.initials: JS
authors.lastname: Salvo
authors.forename: Sorath
authors.initials: S
authors.lastname: Siddiqui
authors.forename: Louise
authors.initials: L
authors.lastname: Mao
authors.forename: Dianna K
authors.initials: DK
authors.lastname: Wheaton
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
authors.forename: Kari E
authors.initials: KE
authors.lastname: Branham
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: Cindy
authors.initials: C
authors.lastname: Wen
authors.forename: Ken
authors.initials: K
authors.lastname: Flagg
authors.forename: Henry
authors.initials: H
authors.lastname: Ferreyra
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Pei
authors.forename: Ayesha
authors.initials: A
authors.lastname: Khan
authors.forename: Huanan
authors.initials: H
authors.lastname: Ren
authors.forename: Keqing
authors.initials: K
authors.lastname: Wang
authors.forename: Irma
authors.initials: I
authors.lastname: Lopez
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
authors.forename: Juan C
authors.initials: JC
authors.lastname: Zenteno
authors.forename: Raul
authors.initials: R
authors.lastname: Ayala-Ramirez
authors.forename: Beatriz
authors.initials: B
authors.lastname: Buentello-Volante
authors.forename: Qing
authors.initials: Q
authors.lastname: Fu
authors.forename: David A
authors.initials: DA
authors.lastname: Simpson
authors.forename: Yumei
authors.initials: Y
authors.lastname: Li
authors.forename: Ruifang
authors.initials: R
authors.lastname: Sui
authors.forename: Giuliana
authors.initials: G
authors.lastname: Silvestri
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Daiger
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
mesh_terms: D000483:Alleles; D019295:Computational Biology; D005091:Exons; D005808:Genes, Recessive; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D012174:Retinitis Pigmentosa / Q000175:diagnosis* / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C105199:CLN3 protein, human; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones