A novel missense mutation in HSF4 causes autosomal-dominant congenital lamellar cataract in a British family

• Published in: Eye (London) 2018-04, Vol.32 (4), p.806-812
• Main Authors: Berry, V, Pontikos, N, Moore, A, Ionides, A C W, Plagnol, V, Cheetham, M E, Michaelides, M
• Format: Article
• Language: English
• Subjects: 45/22; 45/23; 45/47; 631/208; 631/208/212; Blindness; Cataract - genetics; Cataracts; Child; Children; Deoxyribonucleic acid; DNA; Female; Heat Shock Transcription Factors - genetics; Humans; Laboratory Medicine; Laboratory Study; Male; Medicine; Medicine & Public Health; Missense mutation; Mutation; Mutation, Missense; Ophthalmology; Pedigree; Pharmaceutical Sciences/Technology; Surgery; Surgical Oncology; Whole Exome Sequencing
• ISSN: 0950-222X; 1476-5454
• DOI: 10.1038/eye.2017.268

Purpose Inherited cataract, opacification of the lens, is the most common worldwide cause of blindness in children. We aimed to identify the genetic cause of isolated autosomal-dominant lamellar cataract in a five-generation British family. Methods Whole exome sequencing (WES) was performed on two affected individuals of the family and further validated by direct sequencing in family members. Results A novel missense mutation NM_001040667.2:c.190A>G;p.K64E was identified in the DNA-binding-domain of heat-shock transcription factor 4 ( HSF4 ) and found to co-segregate with disease. Conclusion We have identified a novel mutation in HSF4 in a large British pedigree causing dominant congenital lamellar cataract. This is the second mutation in this gene found in the British population. This mutation is likely to be dominant negative and affect the DNA-binding affinity of HSF4.