Revealing hidden genetic diagnoses in the ocular anterior segment disorders

Alan Ma, Saira Yousoof, John R. Grigg, Maree Flaherty, Andre E. Minoche, Mark J. Cowley, Benjamin M. Nash, Gladys Ho, Thet Gayagay, Tiffany Lai, Elizabeth Farnsworth, Emma L. Hackett, Katrina Fisk, Karen Wong, Katherine J. Holman, Gemma Jenkins, Anson Cheng, Frank Martin, Tanya Karaconji, James E. ElderAnnabelle Enriquez, Meredith Wilson, David J. Amor, Chloe A. Stutterd, Benjamin Kamien, John Nelson, Marcel E. Dinger, Bruce Bennetts, Robyn V. Jamieson

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)1623-1632
Number of pages10
JournalGenetics in Medicine
Issue number10
Publication statusPublished - 1 Oct 2020
Externally publishedYes


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