Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features

Mutations in ZFHX1B, encoding Smad-interacting protein 1 (SIP1), have been recently reported to cause a form of Hirschsprung disease (HSCR). Patients with ZFHX1B deficiency typically show mental retardation, delayed motor dev elopment, epilepsy, microcephaly, distinct facial features, and/or congenit al heart disease, in addition to the cardinal form of HSCR. To investigate the breadth of clinical variation, we studied DNA samples from six patients with clinical profiles quite similar to those described elsewhere for ZFHX 1B deficiency, except that they did not have HSCR. The results showed the p reviously reported R695X mutation to be present in three cases, with three novel mutations-a 2-bp insertion (760insCA resulting in 254fs262X), a singl e-base deletion (270delG resulting in 91fs107X), and a 2-bp deletion (2178d elTT resulting in 727fs754X)-newly identified in the other three. All mutat ions occurred in one allele and were de novo events. These results demonstr ate that ZFHX1B deficiency is an autosomal dominant complex developmental d isorder and that individuals with functional null mutations present with me ntal retardation, delayed motor development, epilepsy, and a wide spectrum of clinically heterogeneous features suggestive of neurocristopathies at th e cephalic, cardiac, and vagal levels.