Characterisation of deletions of the ZFHX1B region and genotype-phenotype analysis in Mowat-Wilson syndrome.

In 1998, Mowat et al 1 delineated a syndrome with Hirschsprung disease (HSCR) or severe constipation, microcephaly, mental retardation, and a distinctive facial appearance. Because two of the patients had a cytogenetically visible deletion of 2q22-q23, 2 and all patients were sporadic cases, a contiguous gene syndrome or a dominant single gene disorder involving this locus were suggested. Two similar patients with cytogenetically balanced translocation t(2;13)(q22;q22) and t(2;11)(q22.2;q21), respectively, allowed Wakamatsu et al and Cacheux et al to narrow down the critical interval to 5 Mb and to one single gene respectively, which led both groups independently to the detection of intragenic mutations in the gene coding for Smad interacting protein-1 (formerly SIP1, now called zinc finger homeobox 1B (ZFHX1B)) in patients with so called “syndromic HSCR”. However, because HSCR is not an obligatory symptom and patients with and without HSCR can be recognised by other features, especially their distinct facial gestalt, 6 we suggested that “Mowat-Wilson syndrome” (MWS) is a more appropriate name. Although the developmental ZFHX1B expression pattern fully explains the clinical spectrum observed in patients with Mowat-Wilson syndrome by haploinsufficiency of this gene alone, 7 Wakamatsu et al initially stated that their deletion patient would have a more severe phenotype and therefore would have a contiguous gene syndrome. Amiel et al reported that the phenotype was similar in patients with “syndromic HSCR” caused by mutations and cytogenetically non-visible large scale deletions of the ZFHX1B locus, respectively, but the deletion sizes were not delineated. We therefore analysed deletion size and genotype-phenotype correlation in four new patients with cryptic deletions of the ZFHX1B locus.