Genome sequencing in congenital cataracts improves diagnostic yield

Alan Ma; John R Grigg; Maree Flaherty; James Smith; Andre E Minoche; Mark J Cowley; Benjamin M Nash; Gladys Ho; Thet Gayagay; Tiffany Lai; Elizabeth Farnsworth; Emma L Hackett; Katrina Slater; Karen Wong; Katherine J Holman; Gemma Jenkins; Anson Cheng; Frank Martin; Natasha J Brown; Sarah E Leighton; David J Amor; Himanshu Goel; Marcel E Dinger; Bruce Bennetts; Robyn V Jamieson

doi:10.1002/humu.24240

Genome sequencing in congenital cataracts improves diagnostic yield

Hum Mutat. 2021 Sep;42(9):1173-1183. doi: 10.1002/humu.24240. Epub 2021 Jun 15.

Authors

Alan Ma^{1

2

3}, John R Grigg^{1

4

5

6}, Maree Flaherty^{4

5}, James Smith^{4

5}, Andre E Minoche⁷, Mark J Cowley^{7

8

9}, Benjamin M Nash^{1

3

10}, Gladys Ho^{3

10}, Thet Gayagay¹⁰, Tiffany Lai¹⁰, Elizabeth Farnsworth¹⁰, Emma L Hackett¹⁰, Katrina Slater¹⁰, Karen Wong¹⁰, Katherine J Holman¹⁰, Gemma Jenkins¹⁰, Anson Cheng¹, Frank Martin^{4

5}, Natasha J Brown^{11

12}, Sarah E Leighton¹³, David J Amor^{11

12}, Himanshu Goel¹⁴, Marcel E Dinger^{7

15}, Bruce Bennetts^{3

10}, Robyn V Jamieson^{1

2

3}

Affiliations

¹ Eye Genetics Research Unit, The Children's Hospital at Westmead, Save Sight Institute, Children's Medical Research Institute, University of Sydney, Sydney, New South Wales, Australia.
² Department of Clinical Genetics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
³ Specialties of Genomic Medicine & Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
⁴ Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
⁵ Specialty of Ophthalmology, University of Sydney, Sydney, New South Wales, Australia.
⁶ Save Sight Institute, Sydney Eye Hospital, Sydney, New South Wales, Australia.
⁷ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
⁸ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia.
⁹ St Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Sydney, New South Wales, Australia.
¹⁰ Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
¹¹ Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
¹² Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.
¹³ Tasmanian Clinical Genetics Service, Hobart, Australia.
¹⁴ Hunter Genetics, Newcastle, New South Wales, Australia.
¹⁵ School of Biotechnology and Biomolecular Sciences, Faculty of Science, UNSW, Sydney, New South Wales, Australia.

PMID: 34101287
DOI: 10.1002/humu.24240

Abstract

Congenital cataracts are one of the major causes of childhood-onset blindness around the world. Genetic diagnosis provides benefits through avoidance of unnecessary tests, surveillance of extraocular features, and genetic family information. In this study, we demonstrate the value of genome sequencing in improving diagnostic yield in congenital cataract patients and families. We applied genome sequencing to investigate 20 probands with congenital cataracts. We examined the added value of genome sequencing across a total cohort of 52 probands, including 14 unable to be diagnosed using previous microarray and exome or panel-based approaches. Although exome or genome sequencing would have detected the variants in 35/52 (67%) of the cases, specific advantages of genome sequencing led to additional diagnoses in 10% (5/52) of the overall cohort, and we achieved an overall diagnostic rate of 77% (40/52). Specific benefits of genome sequencing were due to detection of small copy number variants (2), indels in repetitive regions (2) or single-nucleotide variants (SNVs) in GC-rich regions (1), not detectable on the previous microarray, exome sequencing, or panel-based approaches. In other cases, SNVs were identified in cataract disease genes, including those newly identified since our previous study. This study highlights the additional yield of genome sequencing in congenital cataracts.

Keywords: cataracts; genome sequencing; genomics; microphthalmia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cataract* / diagnosis
Cataract* / genetics
Chromosome Mapping
DNA Copy Number Variations / genetics
Exome Sequencing
Exome* / genetics
High-Throughput Nucleotide Sequencing
Humans