Phenotypic and Genetic Spectrum in 309 Consecutive Pediatric Patients with Inherited Retinal Disease

Abstract

Inherited retinal dystrophies (IRDs) are a common cause of blindness or severe visual impairment in children and may occur with or without systemic associations. The aim of the present study is to describe the phenotypic and genotypic spectrum of IRDs in a pediatric patient cohort in Retrospective single-center cross-sectional analysis. Presenting symptoms, clinical phenotype, and molecular genetic diagnosis were assessed in 309 pediatric patients with suspected IRD. Patients were grouped by age at genetic diagnosis (preschool: 0-6 years, n = 127; schoolchildren: 7-17 years, n = 182). Preschool children most frequently presented with nystagmus (34.5% isolated, 16.4% syndromic), no visual interest (20.9%; 14.5%), or nyctalopia (22.4%; 3.6%; p < 0.05); schoolchildren most frequently presented with declining visual acuity (31% isolated, 21.1% syndromic), nyctalopia (10.6%; 13.5%), or high myopia (5.3%; 13.2%). Pathogenic variants were identified in 96 different genes (n = 69 preschool, n = 73 schoolchildren). In the preschool group, 57.4% had isolated and 42.6% had syndromic IRDs, compared to 70.9% and 29.1% in schoolchildren. In the preschool group, 32.4% of the isolated IRDs were related to forms of Leber's congenital amaurosis (most frequent were RPE65 (11%) and CEP290 (8.2%)), 31.5% were related to stationary IRDs, 15.1% were related to macular dystrophies (ABCA4, BEST1, PRPH2, PROM1), and 8.2% to rod-cone dystrophies (RPGR, RPB3, RP2, PDE6A). All rod-cone dystrophies (RCDs) were subjectively asymptomatic at the time of genetic diagnosis. At schoolage, 41% were attributed to cone-dominated disease (34% ABCA4), 10.3% to BEST1, and 10.3% to RCDs (RP2, PRPF3, RPGR; IMPG2, PDE6B, CNGA1, MFRP, RP1). Ciliopathies were the most common syndromic IRDs (preschool 37%; schoolchildren 45.1%), with variants in USH2A, CEP290 (5.6% each), CDH23, BBS1, and BBS10 (3.7% each) being the most frequent in preschoolers, and USH2A (11.7%), BBS10 (7.8%), CEP290, CDHR23, CLRN1, and ICQB1 (3.9% each) being the most frequent in syndromic schoolkids. Vitreoretinal syndromic IRDs accounted for 29.6% (preschool: COL2A1, COL11A1, NDP (5.6% each)) and 23.5% (schoolage: COL2A1, KIF11 (9.8% each)), metabolic IRDs for 9.4% (OAT, HADHA, MMACHD, PMM2) and 3.9% (OAT, HADHA), mitochondriopathies for 3.7% and 7.8%, and syndromic albinism accounted for 5.6% and 3.9%, respectively. In conclusion we show here that the genotypic spectrum of IRDs and its quantitative distribution not only differs between children and adults but also between children of different age groups, with an almost equal proportion of syndromic and non-syndromic IRDs in early childhood. Ophthalmic screening visits at the preschool and school ages may aid even presymptomatic diagnosis and treatment of potential sight and life-threatening systemic sequelae.

Keywords: inherited retinal dystrophy; pediatric patients; syndromic retinal dystrophies.

Figure 1

Modes of inheritance for inherited retinal dystrophies in a molecularly genetically characterized pediatric cohort. Pie charts show the subsets of individuals with diseases associated with X-linked, autosomal dominant (AD), autosomal recessive (AR), and mitochondrial variants. (A) The left panel shows the subsets for the whole pediatric cohort. (B) The middle panel is for the subset of the overall cohort with affected individuals under 6 years. (C) The right-hand panel shows the subset of individuals 7–17 years old at time of genetic diagnosis.

Figure 2

Classification of mutated genes in genetically solved pediatric patients with isolated or syndromic IRDs. (A) shows the distribution of autosomal dominant, (B) X-linked, and (C) autosomal recessive variants. Left panels: infantile cohort, 0–6 years old at time of molecular diagnosis. Right panels: juvenile patients, 7–17 years old at time of molecular diagnosis. The percentage of mutation of each gene is given below the gene.

Figure 3

Diversity of genes carrying causative pathogenic variants in a cohort of pediatric patients with genetically solved syndromic IRD. Mutated genes identified in (A) patients 0–6 years old and (B) 7–17 years old at molecular genetic diagnosis. *, presented with nystagmus, suspected maculopathy, papilledema, and optic disc drusen. The percentage of mutation of each gene is given below the gene.

Figure 4

Flow chart illustrating the clinical diagnostic pathway of the patients in the present study.