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Mol Biol Rep. 2017 Dec;44(6):435-440. doi: 10.1007/s11033-017-4121-4. Epub 2017 Aug 28.

Segregation of a novel p.(Ser270Tyr) MAF mutation and p.(Tyr56∗) CRYGD variant in a family with dominantly inherited congenital cataracts.

Author information

1
Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 128 08, Prague, Czech Republic.
2
Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Katerinska 30, 128 21, Prague, Czech Republic.
3
Gennet, Centre for Fetal Medicine and Reproductive Genetics, Kostelni 9, 170 00, Prague, Czech Republic.
4
Department of Ophthalmology, FMHS, New Zealand National Eye Centre, University of Auckland, 85 Park Rd, Grafton, Auckland, 1023, New Zealand.
5
Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 128 08, Prague, Czech Republic. petra.liskova@lf1.cuni.cz.
6
Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 2, 128 08, Prague, Czech Republic. petra.liskova@lf1.cuni.cz.

Abstract

A bilaterally blind woman, with a three generation family history of autosomal dominant congenital cataracts, variably associated with iris colobomata and microcornea, sought preconception genetic consultation. Whole-exome sequencing was performed in three affected family members, one unaffected first degree relative, and one spouse. The sequence variant c.168C>G; p.(Tyr56∗) in CRYGD, previously reported as pathogenic, and a novel mutation c.809C>A; p.(Ser270Tyr) in MAF, were identified in two affected family members; the grandmother, and half-brother of the proband. The proband inherited only the MAF mutation, whereas her clinically unaffected sister had the CRYGD change. In silico analysis supported a pathogenic role of p.(Ser270Tyr) in MAF, which was absent from publicly available whole-exome datasets, and 1161 Czech individuals. The frequency of CRYGD p.(Tyr56∗) in the ExAC dataset was higher than the estimated incidence of congenital cataract in the general population. Our study highlights that patients with genetically heterogeneous conditions may exhibit rare variants in more than one disease-associated gene, warranting caution with data interpretation, and supporting parallel screening of all genes known to harbour pathogenic mutations for a given phenotype. The pathogenicity of sequence variants previously reported as cataract-causing may require re-assessment in light of recently released datasets of human genomic variation.

KEYWORDS:

CRYGD; Coloboma; Congenital cataract; MAF; Microcornea

PMID:
28849415
DOI:
10.1007/s11033-017-4121-4
[Indexed for MEDLINE]

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