Delimiting the Wolf-Hirschhorn syndrome critical region to 750 kilobase pairs

Abstract

Wolf-Hirschhorn syndrome (WHS) is a multiple anomaly condition characterized by mental and developmental defects, resulting from the absence of the distal segment of one chromosome 4 short arm (4p16.3). Owing to the complex and variable expression of this disorder, it is thought that the WHS is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. The 2.2 Mbp genomic segment previously defined as the critical region by the analyses of patients with terminal or interstitial deletions is extremely gene dense and an intensive investigation of the developmental role of all the genes contained within it would be daunting and expensive. Further refinement in the definition of the critical region would be valuable but depends on available patient material and accurate clinical evaluation. In this study, we have utilized fluorescence in situ hybridization to further characterize a WHS patient previously demonstrated to have an interstitial deletion and demonstrate that the distal breakpoint occurs between the loci FGFR3 and D4S168. This reduces the critical region for this syndrome to less than 750 kbp. This has the effect of eliminating several genes previously proposed as contributing to this syndrome and allows further research to focus on a more restricted region of the genome and a limited set of genes for their role in the WHS syndrome.

Reduced expression by SETBP1 haploinsufficiency causes developmental and expressive language delay indicating a phenotype distinct from Schinzel-Giedion syndrome

“…Mutations in fibroblast growth factor 3 ( FGFR3 ) cause disproportionate growth in achondroplasia by gain-of-function, whereas terminal deletions of 4p including FGFR3 cause Wolff–Hirschhorn syndrome, which does not show disproportionate growth at all, but small stature 13 14. On the other hand, gain-of-function mutations of T-box 1 ( TBX1 ) can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions in 22q11 including TBX1 15…”

Familial Mental Retardation Syndrome ATR-16 Due to an Inherited Cryptic Subtelomeric Translocation, t(3;16)(q29;p13.3)

“…Cytogenetically invisible unbalanced translocations have also been reported to cause other mental retardation syndromes, including Wolf-Hirschhorn syndrome (MIM 194190) (deletion of terminal 4p; Altherr et al 1997), cri-du-chat syndrome (MIM 123450) (deletion of terminal 5p; Overhauser et al 1989), and Miller-Dieker syndrome (MIM 247200) (deletion of terminal 17p; Kuwano et al 1991). In all these syndromes, other phenotypic characteristics, in addition to the mental retardation, contributed to the recognition of the disorder and to the identification of the deletions.…”

Pathogenic significance of deletions distal to the currently described Wolf–Hirschhorn syndrome critical regions on 4p16.3

“…Patients with small 4p deletions have been useful in mapping the clinical features associated with WHS and in defining the critical region(s) where hemizygosity results in a phenotype consistent with the minimal diagnostic criteria for Wolf–Hirschhorn syndrome (WHS) [Estabrooks et al, 1993; White et al, 1995; Altherr et al, 1997; Wright et al, 1997; Rauch et al, 2001; Zollino et al, 2003; Van Buggenhout et al, 2004; Rodriguez et al, 2005; Maas et al, 2008]. These minimal diagnostic criteria include mild to severe developmental delay, hypotonia, intrauterine growth retardation followed by postnatal growth retardation, and the typical facial features of a broad nasal bridge, microcephaly, high forehead with prominent glabella, ocular hypertelorism, epicanthus, highly arched eyebrows, short philtrum, downturned corners of the mouth, micrognathia, and poorly formed ears with pits or tags.…”