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.
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10 October 2017
There was a spacing error in the initial online publication, and there were errors in the Acknowledgments section. The original article has been updated.
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Acknowledgements
This work was supported by Charles University institutional programs UNCE 204011 and PROGRES-Q26/LF1. Specific support was provided by Grants 15-28208A and 17-30500A from the Ministry of Health of the Czech Republic and LQ1604 NPU II from the Ministry of Education of the Czech Republic. We thank The National Center for Medical Genomics (LM2015091) for bioinformatical support with next-generation sequencing data analysis and for providing ethnically matched population genotype frequency data (project CZ.02.1.01/0.0/0.0/16_013/0001634). We thank Jana Kasakova for patients’ referrals and clinical assessment.
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This article has been changed to correctly present the values in the title that uphold the article’s content.
A correction to this article is available online at https://doi.org/10.1007/s11033-017-4130-3.
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Dudakova, L., Stranecky, V., Ulmanova, O. et al. Segregation of a novel p.(Ser270Tyr) MAF mutation and p.(Tyr56∗) CRYGD variant in a family with dominantly inherited congenital cataracts. Mol Biol Rep 44, 435–440 (2017). https://doi.org/10.1007/s11033-017-4121-4
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DOI: https://doi.org/10.1007/s11033-017-4121-4