biostudies-literatureUnknown22(10)Ma A<h4>Purpose</h4>Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion.<h4>Methods</h4>We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases.<h4>Results</h4>We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6.<h4>Conclusions</h4>We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.Genetics in medicine : official journal of the American College of Medical Genetics1623-1632https://www.ebi.ac.uk/biostudies/studies/S-EPMC7521990biostudies-literatureRevealing hidden genetic diagnoses in the ocular anterior segment disorders.PMC7521990Holman KJStutterd CAFlaherty MGrigg JRElder JEWilson MMartin FAmor DJHackett ELYousoof SFisk KWong KFarnsworth EEnriquez AKaraconji TNelson JJenkins GBennetts BCheng ACowley MJJamieson RVHo GGayagay TDinger MEMa AKamien BNash BMMinoche AELai TfalseRevealing hidden genetic diagnoses in the ocular anterior segment disorders.<h4>Purpose</h4>Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion.<h4>Methods</h4>We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases.<h4>Results</h4>We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6.<h4>Conclusions</h4>We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.2020-01-01T00:00:00Z2020 Oct2025-04-22T16:18:09.307Z2025-02-19T01:10:20.734ZS-EPMC75219903249960410.1038/s41436-020-0854-x