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Recently mutations in the gene ZFHX1B (SIP1) were shown in patients with “syndromic Hirschsprung disease” with mental retardation (MR) and multiple congenital anomalies (MCA), but it was unclear if Hirschsprung disease is an obligate symptom of these mutations and if the distinct facial phenotype delineated by Mowat et al. [1998: J Med Genet 35: 617–623] is specific for ZFHX1B mutations. In order to address these open questions we analyzed the ZFHX1B gene in five patients, three of whom had “syndromic Hirschsprung disease” two with and one without the facial phenotype described by Mowat et al. [1998], and two of whom had the distinct facial gestalt without Hirschsprung disease. Analyses of microsatellite markers and newly identified SNPs, and/or FISH with BACs from the ZFHX1B region excluded large deletions in all five patients. Direct sequencing demonstrated truncating ZFHX1B mutations in all four patients with the characteristic facial phenotype, but not in the patient with syndromic Hirschsprung disease without the distinct facial appearance. We demonstrate that there is a specific clinical entity with a recognizable facial gestalt, mental retardation and variable MCAs which we propose be called the “Mowat‐Wilson syndrome.” © 2002 Wiley‐Liss, Inc.

Nonsyndromic X-linked mental retardation (MRX) is defined by an X-linked inheritance pattern of low IQ, problems with adaptive behavior, and the absence of additional specific clinical features. The 13 MRX genes identified to date account for less than one-fifth of all MRX, suggesting that numerous gene defects cause the disorder in other families. In a female patient with severe nonsyndromic mental retardation and a de novo balanced translocation t(X;7)(p11.3;q11.21), we have cloned the DNA fragment that contains the X-chromosomal and the autosomal breakpoint. In silico sequence analysis provided no indication of a causative role for the chromosome 7 breakpoint in mental retardation (MR), whereas, on the X chromosome, a zinc-finger gene, ZNF41, was found to be disrupted. Expression studies indicated that ZNF41 transcripts are absent in the patient cell line, suggesting that the mental disorder in this patient results from loss of functional ZNF41. Moreover, screening of a panel of patients with MRX led to the identification of two other ZNF41 mutations that were not found in healthy control individuals. A proline-to-leucine amino acid exchange is present in affected members of one family with MRX. A second family carries an intronic splice-site mutation that results in loss of specific ZNF41 splice variants. Wild-type ZNF41 contains a highly conserved transcriptional repressor domain that is linked to mechanisms of chromatin remodeling, a process that is defective in various other forms of MR. Our results suggest that ZNF41 is critical for cognitive development; further studies aim to elucidate the specific mechanisms by which ZNF41 alterations lead to MR.

To define the range of phenotypic expression in Treacher Collins syndrome (TCS; Franceschetti-Klein syndrome), we performed mutation analysis in the TCOF1 gene in 46 patients with tentative diagnosis of TCS and evaluated the clinical data, including a scoring system. A total of 27 coding exons of TCOF1 and adjacent splice junctions were analysed by direct sequencing. In 36 patients with a clinically unequivocal diagnosis of TCS, we detected 28 pathogenic mutations, including 25 novel alterations. No mutation was identified in the remaining eight patients with unequivocal diagnosis of TCS and 10 further patients, in whom the referring diagnosis of TCS was clinically doubtful. There is no overt genotype-phenotype correlation except that conductive deafness is significantly less frequent in patients with mutations in the 3 0 part of the open reading frame. Inter-and intrafamilial variation is wide. Some mutation carriers, parents of typically affected patients, are so mildly affected that the diagnosis might be overlooked clinically. This suggests that modifying factors are important for phenotypic expression. Based on these findings, minimal diagnostic criteria were defined: downward slanting palpebral fissures and hypoplasia of the zygomatic arch. The difficulties in genetic counselling, especially diagnosis of family members with a mild phenotype, are described.