TY - JOUR
T1 - Frequency and Genetic Spectrum of Inherited Retinal Dystrophies in a Large Dutch Pediatric Cohort
T2 - The RD5000 Consortium
AU - Heutinck, Pam A.T.
AU - van den Born, L. Ingeborgh
AU - Vermeer, Maikel
AU - Iglesias Gonzales, Adriana I.
AU - Hoyng, Carel B.
AU - Pott, Jan Willem R.
AU - Kroes, Hester Y.
AU - van Schooneveld, Mary J.
AU - Boon, Camiel J.F.
AU - van Genderen, Maria M.
AU - Plomp, Astrid S.
AU - de Jong-Hesse, Yvonne
AU - van Egmond-Ebbeling, Michelle B.
AU - Hoefsloot, Lies H.
AU - A Bergen, Arthur
AU - Klaver, Caroline C.W.
AU - Meester-Smoor, Magda A.
AU - Thiadens, Alberta A.H.J.
AU - Verhoeven, Virginie J.M.
N1 - Publisher Copyright:
Copyright 2024 The Authors.
PY - 2024/8/1
Y1 - 2024/8/1
N2 - Purpose: Gene-based therapies for inherited retinal dystrophies (IRDs) are upcoming. Treatment before substantial vision loss will optimize outcomes. It is crucial to identify common phenotypes and causative genes in children. This study investigated the frequency of these in pediatric IRD with the aim of highlighting relevant groups for future therapy. Methods:Diagnostic, genetic, and demographic data, collected from medical charts of patients with IRD aged up to 20 years (n = 624, 63% male), registered in the Dutch RD5000 database, were analyzed to determine frequencies of phenotypes and genetic causes. Phenotypes were categorized as nonsyndromic (progressive and stationary IRD) and syndromic IRD. Genetic causes, mostly determined by whole-exome sequencing (WES), were examined. Additionally, we investigated the utility of periodic reanalysis of WES data in genetically unresolved cases.Results: Median age at registration was 13 years (interquartile range, 9-16). Retinitis pigmentosa (RP; n = 123, 20%), Leber congenital amaurosis (LCA; n = 97, 16%), X-linked retinoschisis (n = 64, 10%), and achromatopsia (n = 63, 10%) were the most frequent phenotypes. The genetic cause was identified in 76% of the genetically examined patients (n = 473). The most frequently disease-causing genes were RS1 (n = 32, 9%), CEP290 (n = 28, 8%), CNGB3 (n = 21, 6%), and CRB1 (n = 17, 5%). Diagnostic yield after reanalysis of genetic data increased by 7%. Conclusions: As in most countries, RP and LCA are the most prominent pediatric IRDs in the Netherlands, and variants in RS1 and CEP290 were the most prominent IRD genotypes. Our findings can guide therapy development to target the diseases and genes with the greatest needs in young patients.
AB - Purpose: Gene-based therapies for inherited retinal dystrophies (IRDs) are upcoming. Treatment before substantial vision loss will optimize outcomes. It is crucial to identify common phenotypes and causative genes in children. This study investigated the frequency of these in pediatric IRD with the aim of highlighting relevant groups for future therapy. Methods:Diagnostic, genetic, and demographic data, collected from medical charts of patients with IRD aged up to 20 years (n = 624, 63% male), registered in the Dutch RD5000 database, were analyzed to determine frequencies of phenotypes and genetic causes. Phenotypes were categorized as nonsyndromic (progressive and stationary IRD) and syndromic IRD. Genetic causes, mostly determined by whole-exome sequencing (WES), were examined. Additionally, we investigated the utility of periodic reanalysis of WES data in genetically unresolved cases.Results: Median age at registration was 13 years (interquartile range, 9-16). Retinitis pigmentosa (RP; n = 123, 20%), Leber congenital amaurosis (LCA; n = 97, 16%), X-linked retinoschisis (n = 64, 10%), and achromatopsia (n = 63, 10%) were the most frequent phenotypes. The genetic cause was identified in 76% of the genetically examined patients (n = 473). The most frequently disease-causing genes were RS1 (n = 32, 9%), CEP290 (n = 28, 8%), CNGB3 (n = 21, 6%), and CRB1 (n = 17, 5%). Diagnostic yield after reanalysis of genetic data increased by 7%. Conclusions: As in most countries, RP and LCA are the most prominent pediatric IRDs in the Netherlands, and variants in RS1 and CEP290 were the most prominent IRD genotypes. Our findings can guide therapy development to target the diseases and genes with the greatest needs in young patients.
UR - http://www.scopus.com/inward/record.url?scp=85202551727&partnerID=8YFLogxK
U2 - 10.1167/iovs.65.10.40
DO - 10.1167/iovs.65.10.40
M3 - Article
C2 - 39189993
AN - SCOPUS:85202551727
SN - 0146-0404
VL - 65
SP - 40
JO - Investigative ophthalmology & visual science
JF - Investigative ophthalmology & visual science
IS - 10
M1 - 40
ER -