Human Molecular Genetics Advance Access originally published online on May 4, 2009
Human Molecular Genetics 2009 18(14):2643-2655; doi:10.1093/hmg/ddp206
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X-linked cataract and Nance-Horan syndrome are allelic disorders
1 UCL Institute of Ophthalmology, London, UK 2 Department of Clinical Genetics, Yorkhill Hospital, Glasgow, UK 3 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada 4 Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway 5 Department of Ophthalmology, Innland Hospital, Elverum, Norway 6 St George's Hospital, London, UK 7 Addenbrooke's Hospital, Cambridge, UK 8 West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham, UK 9 Moorfields Eye Hospital, City Road, London, UK 10 Ulverscroft Vision Research Group, Great Ormond Street Hospital for Children, London, UK
* To whom correspondence should be addressed at: UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK. Tel: +44 2076086945; Fax: +44 2076084002; Email: a.hardcastle{at}ucl.ac.uk
Received February 19, 2009; Revised April 7, 2009; Accepted April 28, 2009
Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication–triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved.
Present address: M.B.: BC Women's and Children's Hospital, Vancouver, Canada; H.A.Y.: The Genetics Clinic, Calgary, Canada; P.F.: Casey Eye Institute, Portland, OR, USA.