{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T03:16:16Z","timestamp":1768533376672,"version":"3.49.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Congenital cataract (CC), defined as lens opacity present at birth or in early infancy, is a major cause of reversible childhood blindness and shows marked genetic heterogeneity. This study aimed to investigate the genetic basis of CC in a multigenerational Chinese family.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A four-generation family with CC was clinically characterized. Whole-exome sequencing was performed in the proband, followed by stepwise variant filtering based on minor allele frequency, predicted functional impact, known CC-associated genes, and an autosomal dominant inheritance model. Candidate variants were annotated and classified according to ACMG guidelines. Sanger sequencing was used to validate variants in two additional affected relatives.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Two heterozygous missense variants were identified in known CC-associated genes:\n                      <jats:italic>GJA3<\/jats:italic>\n                      c.776C &amp;gt; A (p.Ser259Tyr) and\n                      <jats:italic>CRYBA1<\/jats:italic>\n                      c.346A &amp;gt; T (p.Ile116Phe). Both were extremely rare or absent in population databases and predicted to be damaging by multiple in silico tools. Sanger sequencing confirmed that the two variants co-occurred in all three affected family members tested, and no other rare, protein-altering variants meeting the filtering criteria were found in established cataract genes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>According to ACMG guidelines, both variants remain classified as variants of uncertain significance, but their rarity, predicted functional impact and consistent co-occurrence in affected individuals support them as strong candidate variants that may jointly contribute to CC in this family and expand the spectrum of GJA3- and CRYBA1-associated changes.<\/jats:p>\n                  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