ABCA4 Versus PRPH2-Associated Retinopathy: Clinical and Electrophysiological Findings.
Journal
Investigative ophthalmology & visual science
Journal Volume
67
Journal Issue
4
Start Page
Art. No. 29
ISSN
1552-5783
Date Issued
2026-04-01
Author(s)
Heath Jeffery, Rachael C
Thompson, Jennifer A
Lo, Johnny
Vincent, Andrea L
Patil, Minal
Bianco, Lorenzo
Battaglia Parodi, Maurizio
Ziccardi, Lucia
Dell'Aquila, Carmen
Barbano, Lucilla
Tang, Wei Chao
Chan, Choi Mun
Boon, Camiel J F
Hensman, Jonathan
Lin, Chien-Yu
Vincent, Ajoy
Tumber, Anupreet
Heon, Elise
Grigg, John R
Jamieson, Robyn V
Cornish, Elisa E
Nash, Benjamin M
Chou, Jeremy
Lamey, Tina M
McLenachan, Samuel
Roshandel, Danial
Fujinami, Kaoru
Chelva, Enid
McLaren, Terri L
Chen, Fred K
Abstract
Background: Inherited retinal degeneration (IRD) comprises a diverse group of monogenic disorders characterized by marked genetic and phenotypic heterogeneity. Although next-generation sequencing (NGS) enables the identification of candidate variants, many remain classified as variants of uncertain significance (VUS). Ancestry-matched population data can strengthen comparative evidence, and the emergence of national biobanks provides new opportunities to operationalize ACMG/AMP criterion PS4 through case-control analyses.
Methods: We integrated an IRD cohort of 802 probands with whole-genome allele frequency data from 1,492 individuals in the Taiwan Biobank. An allele-based case-control framework was applied, assigning PS4 when the Haldane-Anscombe-corrected odds ratio was ≥ 5 and the 95% confidence interval excluded 1. Post-PS4 triage required variants to: (i) reside in IRD-associated genes, (ii) be rare in East Asian populations in gnomAD v4.1, and (iii) be annotated in RefSeq as exonic, untranslated regions, or splicing (± 20 bp). Baseline ACMG/AMP classifications were generated using GeneBe and finalized through expert curation.
Results: Incorporation of PS4 substantially refined variant interpretation, upgrading two variants from Likely Pathogenic to Pathogenic and six from VUS to Likely Pathogenic. Homozygous exemplar variants, including CNGB1 (NM_001297.5): c.2921T > G and CFAP410 (NM_004928.3): c.340_351dup, demonstrated strong genotype-phenotype concordance with confirmatory sequencing, illustrating an end-to-end workflow from statistical enrichment to clinical reporting.
Conclusion: An ancestry-aware case-control framework enables effective implementation of PS4 and improves the accuracy of IRD variant classification. This reproducible strategy supports the integration of population-specific genomic data into clinical workflows and is applicable to other monogenic disorders.
Subjects
ACMG/AMP classification
Ancestry-matched controls
Inherited retinal degeneration
PS4 (case–control enrichment)
Taiwan biobank
Variant interpretation
Publisher
Association for Research in Vision and Ophthalmology Inc.
Type
journal article