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Revealing hidden genetic diagnoses in the ocular anterior segment disorders

Ma A 1 , Yousoof S 1 , Grigg JR 1 , Flaherty M 2 , Minoche AE 3 , Cowley MJ 3 Show all authors , Nash BM 1 , Ho G 4 , Gayagay T 5 , Lai T 5 , Farnsworth E 5 , Hackett EL 5 , Fisk K 5 , Wong K 5 , Holman KJ 5 , Jenkins G 5 , Cheng A 1 , Martin F 2 , Karaconji T 2 , Elder JE 6 , Enriquez A 7 , Wilson M 7 , Amor DJ 8 , Stutterd CA 8 , Kamien B 9 , Nelson J 10 , Dinger ME 3 , Bennetts B 4 , Jamieson RV 11

Affiliations 

  • 1 Eye Genetics Research Unit, The Children's Hospital at Westmead, Save Sight Institute, Children's Medical Research Institute, University of Sydney, Sydney, NSW, Australia
  • 2 Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, NSW, Australia
  • 3 Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  • 4 Disciplines of Genomic Medicine & Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
  • 5 Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia
  • 6 Department of Ophthalmology, Royal Children's Hospital, Parkville, VIC, Australia
  • 7 Department of Clinical Genetics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia
  • 8 Murdoch Children's Research Institute and University of Melbourne, Melbourne, VIC, Australia
  • 9 Hunter Genetics, Newcastle, NSW, Australia
  • 10 Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA, Australia
  • 11 Eye Genetics Research Unit, The Children's Hospital at Westmead, Save Sight Institute, Children's Medical Research Institute, University of Sydney, Sydney, NSW, Australia. [email protected]
Genet Med, 2020 10;22(10):1623-1632.
PMID: 32499604 DOI: 10.1038/s41436-020-0854-x

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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