Complete deletion of ornithine transcarbamylase gene confirmed by CGH array of X chromosome

Ornithine transcarbamylase deficiency is an X-linked semidominant trait that is the most frequent inborn error of the urea cycle. Three hundred and fifty different mutations, including mostly point mutations and a small proportion of large rearrangements have been reported. Conventional molecular diagnosis is highly reliable for point mutations but can miss gross rearrangements. We describe a contiguous gene syndrome involving the RPGR, OTC and TM4SF2 genes in a male patient with severe neonatal OTC deficiency identified by the conventional molecular approach. Molecular characterization was ascertained by X chromosome CGH array and confirmed by MLPA. Complete deletion of the OTC gene led to absent OTC enzymatic activity in liver and to a severe clinical phenotype. The maternal phenotype, characterized by less severe hyperammonaemic crises associated with neurological impairment would result from a deficient but not null OTC activity due to random X chromosome inactivation in the liver. Our cases are similar toothers described presenting with OTC deficient phenotype in which OTC and contiguous genes are affected. Clinical expression would be conditioned by complete OTC deficiency in males and by X chromosome inactivation in females, leading to compensation by the normal allele in tissues such as blood or muscle but not sufficiently in liver. The application of high-resolution genetic techniques allows the characterization of causative mutations such as large deletions in order to guide genetic counselling and prenatal diagnosis.