Clinical and Genetic Spectrum of Pediatric IRDs in Portugal: Data from the IRD-PT Registry
DOI:
https://doi.org/10.48560/rspo.32932Keywords:
Child, Genetic Diseases, Inborn, Genetic Testing, Retinal Dystrophies/geneticsAbstract
INTRODUCTION: Inherited retinal dystrophies (IRDs) are a major cause of childhood blindness, but to date, no national population-based study regarding the clinical and genetic spectrum of these disorders has been conducted. Thus, this study aimed to characterize the clinical and molecular spectrum of pediatric IRDs in Portugal.METHODS: Multicenter, cross-sectional, cohort study of consecutive 79 pediatric patients (age < 18 years old), 70 of which unrelated, with a clinical diagnosis of IRD and available genetic testing results, identified via the IRD-PT registry. Phenotype parameters included age of onset, first visual symptom and clinical phenotype based on ophthalmological examination and deep phenotyping. Genetic testing was clinically oriented in all probands and included Sanger sequencing, next-generation sequencing (NGS) or whole exome sequencing (WES)-based panels. Variants were classified in accordance with the American College of Medical Genetics and Genomics (ACMG). Only pathogenic (class V) or likely pathogenic (class IV) variants were considered to establish a molecular diagnosis.
RESULTS: A genetically confirmed diagnosis was achieved in 56/70 (80.0%) families. The most prevalent diagnoses were rod-cone dystrophy (RCD) in 15 patients and cone/cone-rod dystrophy (COD/CORD) in 14 patients. Leber congenital amaurosis (LCA) and albinism were observed in 7 subjects each, X-linked retinoschisis (XLRS) in 6, Usher syndrome in 6, Best disease and achromatopsia in 4 each, Bardet-Biedl syndrome (BBS) in 3, Stickler syndrome, congenital stationary night blindness (CSNB) and Heimler syndrome in 2, and Stargardt disease (STGD), KearnsSayre syndrome (KSS), Cohen syndrome, hypotrichosis with juvenile macular dystrophy (HJMD), methylmalonic aciduria (MMA), Liberfarb disease and neuropathy, ataxia and retinitis pigmen- tosa (NARP) syndrome in 1 subject each. Almost 2/3 (65.8%) of patients initiated symptoms before 6 years old, with nystagmus and vision loss being the most frequently reported symptoms. A total of 59 disease-causing variants were identified distributed across 34 different genes, with ABCA4 (n=5 families) and RS1 (n=5) being the most frequently mutated genes.
CONCLUSION: Our results shed light on the clinical and genomic landscape of pediatric IRDs in Portugal. The fact that the majority of children-initiated symptoms before 6 years old highlights the importance of a high level of suspicion to establish an early diagnosis.
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