Eye Genetics Research Unit, The Children's Hospital at Westmead, Save Sight Institute, Children's Medical Research Institute, University of Sydney, Sydney, NSW, Australia.
Department of Clinical Genetics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia.
Genet Med. 2020 Oct;22(10):1623-1632. doi: 10.1038/s41436-020-0854-x. Epub 2020 Jun 5.
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.
眼前节疾病（ASD）在临床上和遗传学上具有异质性，遗传诊断往往难以确定。在本研究中，我们展示了使用表型、基因组和家系结构数据进行综合分析方案以得出遗传结论的价值。
我们利用染色体微阵列、外显子组测序和基因组测序与结构变异和 trio 分析相结合的方法，对 41 例主要散发性病例进行了研究。
我们在 54%（22/41）的病例中鉴定出可能的致病变异，包括 51%（19/37）的散发性病例和 75%（3/4）的最初被认为是家族性 ASD 的病例。三分之二的散发性病例发现存在杂合变异，这些变异在大多数情况下是新生的。大约三分之一（7/22）的遗传诊断是在罕见报道或最近发现的 ASD 基因中发现的，包括 PXDN、GJA8、COL4A1、ITPR1、CPAMD8，以及 Axenfeld-Rieger 异常与纯合 ADAMTS17 变异的新表型关联。其余的变异发生在关键的 ASD 基因中，包括 FOXC1、PITX2、CYP1B1、FOXE3 和 PAX6。
我们证明了详细的表型、基因组、变异和分离分析的益处，可以揭示一些以前在几个罕见报道和新发现的与眼部 ASD 相关疾病基因中“隐藏”的可遗传答案。
