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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\u2013control analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2013control framework was applied, assigning PS4 when the Haldane\u2013Anscombe\u2013corrected odds ratio was \u2265\u20095 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 (\u00b1\u200920\u00a0bp). Baseline ACMG\/AMP classifications were generated using GeneBe and finalized through expert curation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>CNGB1<\/jats:italic>\n                      (NM_001297.5): c.2921T\u2009&gt;\u2009G and\n                      <jats:italic>CFAP410<\/jats:italic>\n                      (NM_004928.3): c.340_351dup, demonstrated strong genotype\u2013phenotype concordance with confirmatory sequencing, illustrating an end-to-end workflow from statistical enrichment to clinical reporting.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>An ancestry-aware case\u2013control 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40246-026-00923-0","type":"journal-article","created":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T06:33:14Z","timestamp":1771137194000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From enrichment to interpretation: PS4-driven reclassification in Taiwanese inherited retinal degeneration"],"prefix":"10.1186","volume":"20","author":[{"given":"Yu-Shu","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chien-Yu","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-An","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chieh-Yu","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang-Hao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob Shujui","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ta-Ching","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei-Lung","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,15]]},"reference":[{"key":"923_CR1","doi-asserted-by":"publisher","first-page":"a017111","DOI":"10.1101\/cshperspect.a017111","volume":"5","author":"JA Sahel","year":"2015","unstructured":"Sahel JA, Marazova K, Audo I. 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