Further delineation of the phenotype associated with heterozygous mutations in <i>ZFHX1B</i>

Mutations or deletions involving ZFHX1B (previously SIP1) have recently been found to cause one form of syndromic Hirschsprung disease (HSCR), associated with microcephaly, mental retardation, and distinctive facial features. Patients with the characteristic facial phenotype and severe mental retardation, but without HSCR, have now also been shown to have mutations in this gene. Mutations of ZFHX1B are frequently associated with other congenital anomalies, including congenital heart disease, hypospadias, renal tract anomalies, and agenesis of the corpus callosum (ACC). We present the clinical data and mutation analysis results from a series of 23 patients with this clinical syndrome, of whom 21 have proven ZFHX1B mutations or deletions (15 previously unpublished). Two patients with the typical features (one with and one without HSCR) did not have detectable abnormalities of ZFHX1B. We emphasize that this syndrome can be recognized by the facial phenotype in the absence of either HSCR or other congenital anomalies, and needs to be considered in the differential diagnosis of dysmorphism with severe mental retardation +/- epilepsy.