Clinical and molecular analysis of Mowat-Wilson syndrome associated with <i>ZFHX1B</i> mutations and deletions at 2q22–q24.1

irschsprung disease (HSCR), a clinically complex syndrome often associated with a combination of mental retardation, microcephaly, and characteristic facial features, is genetically heterogeneous. 1-10 Recently, mutations in ZFHX1B, which encodes Smad-interacting protein 1 (SIP1), were identified by our group 11 and Cacheux et al 12 in patients with t(2;13)(q22;q22) and t(2;11)(q22.2;q21), respectively. These patients had clinical profiles consistent with a dominant form of the disease (Mowat-Wilson syndrome: MIM 235730). 9 13 These and subsequent articles have demonstrated a link between patients with nonsense and frameshift mutations of the gene and the presence in these patients of the following clinical findings: profound mental retardation, delayed motor development, and specific facial features, including hypertelorism, a broad nasal bridge, strabismus, a pointed chin, prognathism, a nose with a prominent columella, and posteriorly rotated ears. 4] Thus, ZFHX1B clearly plays a critical role in the manifestation of clinical features of Mowat-Wilson syndrome. However, several points remain to be elucidated: (1) How broad are the clinical features in patients with ZFHX1B mutations and deletions? (2) What are the underlying molecular mechanisms by which the deletion of ZFHX1B at 2q22 affects the clinical phenotype? (3) What kind of clinical features might appear if the deletions were extended to include 2q23-q24.1? To address these questions, we have characterized the clinical features and underlying molecular basis of 27 cases with mutations or deletions in ZFHX1B, including 12 previously reported cases comprising 10 mutations, one deletion, and another case that had previously been found to have neither a deletion nor a mutation in the gene.