Contiguous gene deletion involving L1CAM and AVPR2 causes X-linked hydrocephalus with nephrogenic diabetes insipidus

X-linked hydrocephalus with aqueductal stenosis (HSAS) is caused by mutation or deletion of the L1 cell adhesion molecule gene (L1CAM) at Xq28. Central diabetes insipidus (CDI) can arise as a consequence of resultant hypothalamic dysfunction from hydrocephalus and must be distinguished from nephrogenic diabetes insipidus (NDI) by exogenous vasopressin response. Causes of NDI are heterogeneous and include mutation or deletion of the arginine vasopressin receptor 2 gene (AVPR2), which is located ∼29 kb telomeric to L1CAM. We identified a patient with both HSAS and NDI where DNA sequencing failure suggested the possibility of a contiguous gene deletion. A 32.7 kb deletion mapping from L1CAM intron1 to AVPR2 exon2 was confirmed. A 90 bp junctional insertion fragment sharing short direct repeat homology with flanking sequences was identified. To our knowledge this is the first reported case of an Xq28 microdeletion involving both L1CAM and AVPR2, defining a new contiguous gene syndrome comprised of HSAS and NDI. Contiguous gene deletion should he considered as a mechanism for all patients presenting with hydrocephalus and NDI.