Clin Genet 2013: 84: 378 – 381 Printed in Singapore. All rights reserved  2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12158 Short Report A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family Brice G, Ostergaard P, Jeffery S, Gordon K, Mortimer PS, Mansour S. A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family. Clin Genet 2013: 84: 378–381.  John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2013 Oculodentodigital syndrome (ODD; OMIM 164200) is a congenital condition with phenotypic features most commonly affecting the face, eyes, dentition and digits. The condition is caused by mutations in the GJA1 gene on chromosome 6. GJA1 codes for connexin 43, a gap junction protein important in providing cell to cell communication and is expressed in lymphatic valves. We present a patient with a clinical and molecular diagnosis of ODD and lower limb lymphoedema. Sanger sequencing of family members confirmed that the missense, p.K206R, GJA1 mutation segregated with the phenotype suggestive of causality. To our knowledge this association has not been reported previously. This is therefore the second connexin gene associated with a lymphoedema phenotype after the recent publication of GJC2 (connexin 47) as a cause of four limb lymphoedema. Conflict of interest All authors declare no conflict of interest. G Brice a , P Ostergaard b , S Jeffery b , K Gordon c , PS Mortimer c and S Mansour a a SW Thames Regional Genetics Service, b Human Genetics Research Centre, Biomedical Sciences, and c Department of Clinical Sciences, St George’s University of London, London SW17 0RE, UK Key words: connexin 43 – GJA1 – lymphoedema – oculodentodigital syndrome – ODD syndrome Corresponding author: Dr Glen Brice, SW Thames Regional Genetics Service, St George’s University of London, London SW17 0RE, UK. Tel.: 0208 725 0957; fax: 0208 725 3444; e-mail: gbrice@sgul.ac.uk Received 20 February 2013, revised and accepted for publication 27 March 2013 Oculodentodigital syndrome (ODD; OMIM 164200) is a congenital condition with phenotypic features affect- ing the face, eyes, dentition and digits. Characteristic findings include hypotelorism, hypoplastic alae nasi, microphthalmia, microcornea, microdontia, enamel hypoplasia, and digital anomalies including syndactyly of the fourth and fifth fingers. Other reported features include glaucoma, poor hair growth, and conductive hearing loss. Neurological manifestations, e.g. spas- tic gait, incontinence and epilepsy have also been reported (1, 2). The mode of inheritance is most often autosomal dominant, but rare autosomal recessive families and sporadic cases have been reported (2). ODD is caused by mutations in the connexin 43 gene (GJA1 ), one of more than 20 connexins expressed in humans. Connexins code for gap junction proteins which assist in cell to cell adhesion and provide for direct inter- cellular communication by providing a low resistance intercellular passage for ions and small molecules (3). There are no distinct phenotype–genotype correlations but if an individual has two or less of the key ODD features then they are less likely to have a mutation in GJA1 (2). To our knowledge, lymphoedema has not previously been reported in association with ODD syndrome. In a Mutation Update, Paznekas et al. (2) give a compre- hensive overview of published GJA1 mutations, and all features that are associated with ODD. Lymphoedema is not reported. Likewise, a PubMed search failed to find any cases of ODD with lymphoedema. Here we present a family with a clear ODD phenotype along with lymphoedema, and molecular confirmation of a GJA1 mutation. This is therefore the first report of lymphoedema associated with a GJA1 mutation but, notably, the second connexin gene reported to produce lymphoedema. 378