Mild Wolf-Hirschhorn syndrome: micro-array CGH analysis of atypical 4p16.3 deletions enables refinement of the genotype-phenotype map

Wolf-Hirschhorn syndrome is a multiple malformation syndrome with distinct abnormal craniofacial features, prenatal onset growth retardation, failure to thrive, microcephaly, usually severe mental retardation, seizures, and congenital heart malformations. Large variations are observed in phenotypic expression of these features, with mental retardation ranging from severe to mild. There is a one third mortality in the first two years of life. Most patients with Wolf-Hirschhorn syndrome carry 4p terminal deletions. However, the size of these deletions is variable and several phenotypic features have been tentatively mapped within the 4pter region.1–4 Further fine mapping of the different phenotypic features will ultimately lead to a functional understanding of the genes that cause these abnormal phenotypes. The minimal ‘Wolf-Hirschhorn syndrome’ phenotype was defined as the typical facial appearance, congenital hypotonia, mental retardation, growth delay, and seizures.2,4 The Wolf-Hirschhorn syndrome critical region was originally confined to a region of 165 kb and nine transcripts within this region were described.5 A patient with a small intrachromosomal 4p deletion and a partial Wolf-Hirschhorn syndrome phenotype further refined the critical region (WHSCR1).6 Two genes, the Wolf-Hirschhorn Syndrome Candidate genes 1 (WHSC1) and 2 (WHSC2), are located in the region. The expression pattern of WHSC1 colocalises spatially and temporarily with the major Wolf-Hirschhorn syndrome malformations and the gene is homologous with a Drosophila dysmorphology gene.7 WHSC2 is a nuclear protein with a helix-loop-helix motif that is ubiquitously expressed throughout development.8,9 The identification of a Wolf-Hirschhorn syndrome patient with a terminal 1.9 Mb deletion not including this Wolf-Hirschhorn syndrome critical region led Zollino et al4 to postulate a novel critical region distal to the previously defined critical region, which was termed the Wolf-Hirschhorn critical region 2 (WHSCR2). The distal boundary of this region is located within the WHSCR1 and at …