1. ¹Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, NE1 4LP, UK
2. ²MRC Human Genetics Unit, Western General Hospital, Edinburgh, EH4 2XU, UK
3. ³Regional Molecular Genetics Laboratory, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK
4. ⁴University of Edinburgh School of Molecular and Clinical Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK
5. ⁵Department of Clinical and Experimental Epilepsy, Institute of Neurology, UCL, Queen Square, London WC1N 3BG, UK

Correspondence: Dr RA Henderson, Northern Genetics Service, Institute of Human Genetics, Centre for Life, Newcastle upon Tyne NE1 4BZ, UK. Tel: +44 191 241 8750; Fax: +44 191 241 8799; E-mail: alexhenderson@doctors.org.uk

Received 27 November 2006; Revised 16 February 2007; Accepted 21 February 2007; Published online 4 April 2007.

Abstract

A girl with aniridia, microphthalmia, microcephaly and café au lait macules was found to have mutations in PAX6, NF1 and OTX2. A novel PAX6 missense mutation (p.R38W) was inherited from her mother whose iris phenotype had not been evident because of ocular neurofibromatosis. Analysis of the NF1 gene in the proband, prompted by the mother's diagnosis and the presence of café au lait spots, revealed a nonsense mutation (p.R192X). Subsequently an OTX2 nonsense mutation (p.Y179X) was identified and shown to be inherited from her father who was initially diagnosed with Leber's congenital amaurosis. Since individual mutations in PAX6, OTX2 or NF1 can cause a variety of severe developmental defects, the proband's phenotype is surprisingly mild. This case shows that patients with complex phenotypes should not be eliminated from subsequent mutation analysis after one or even two mutations are found.