Revealing hidden genetic diagnoses in the ocular anterior segment disorders

遗传学 外显子组测序 生物 拷贝数变化 6号乘客 遗传异质性 表型 染色体 遗传分析 基因 候选基因 外显子组 基因组 转录因子
作者
Alan Ma,Saira Yousoof,John Grigg,Maree Flaherty,André E. Minoche,Mark J. Cowley,Benjamin M. Nash,Gladys Ho,Thet Gayagay,Tiffany Lai,Elizabeth Farnsworth,Emma L. Hackett,Katrina Fisk,Karen Wong,Katherine Holman,Gemma Jenkins,Anson Cheng,Frank Martin,Tanya Karaconji,James E. Elder,Annabelle Enriquez,Meredith Wilson,David J. Amor,Chloe Stutterd,Benjamin Kamien,John W. Nelson,Marcel E. Dinger,Bruce Bennetts,Robyn V. Jamieson
出处
期刊:Genetics in Medicine [Elsevier BV]
卷期号:22 (10): 1623-1632 被引量:41
标识
DOI:10.1038/s41436-020-0854-x
摘要

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.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.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.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.
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