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Pathogenic variants in the CYP21A2 gene cause isolated autosomal dominant congenital posterior polar cataracts

Berry, V; Pontikos, N; Ionides, A; Kalitzeos, A; Quinlan, RA; Michaelides, M; (2021) Pathogenic variants in the CYP21A2 gene cause isolated autosomal dominant congenital posterior polar cataracts. Ophthalmic Genetics 10.1080/13816810.2021.1998556.

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Abstract

Background: Congenital cataracts are the most common cause of visual impairment worldwide. Inherited cataract is a clinically and genetically heterogeneous disease. Here we report disease-causing variants in a novel gene, CYP21A2, causing autosomal dominant posterior polar cataract. Variants in this gene are known to cause autosomal recessive congenital adrenal hyperplasia (CAH). Methods: Using whole-exome sequencing (WES), we have identified disease-causing sequence variants in two families of British and Irish origin, and in two isolated cases of Asian-Indian and British origin. Bioinformatics analysis confirmed these variants as rare with damaging pathogenicity scores. Segregation was tested within the families using direct Sanger sequencing. Results: A nonsense variant NM_000500.9 c.955 C > T; p.Q319* was identified in CYP21A2 in two families with posterior polar cataract and in an isolated case with unspecified congenital cataract phenotype. This is the same variant previously linked to CAH and identified as Q318* in the literature. We have also identified a rare missense variant NM_000500.9 c.770 T > C; p.M257T in an isolated case with unspecified congenital cataract phenotype. Conclusion: This is the first report of separate sequence variants in CYP21A2 associated with congenital cataract. Our findings extend the genetic basis for congenital cataract and add to the phenotypic spectrum of CYP21A2 variants and particularly the CAH associated Q318* variant. CYP21A2 has a significant role in mineralo- and gluco-corticoid biosynthesis. These findings suggest that CYP21A2 may be important for extra-adrenal biosynthesis of aldosterone and cortisol in the eye lens.

Type: Article
Title: Pathogenic variants in the CYP21A2 gene cause isolated autosomal dominant congenital posterior polar cataracts
DOI: 10.1080/13816810.2021.1998556
Publisher version: https://doi.org/10.1080/13816810.2021.1998556
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Congenital posterior polar cataract, congenital cataracts, WES, cytochromes P450, ADRENAL-HYPERPLASIA, 21-HYDROXYLASE DEFICIENCY, STEROL SYNTHESIS, MUTATIONS, LENS, ALDOSTERONE, CHOLESTEROL, HOMEOSTASIS, EVOLUTION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10138515
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