A Transcript Map of the Newly Defined 165 kb Wolf-Hirschhorn Syndrome Critical Region

Abstract

Wolf-Hirschhorn syndrome (WHS) is a multiple malformation syndrome characterised by mental and developmental defects resulting from the absence of a segment of one chromosome 4 short arm (4p16.3). Due 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. In an effort to identify genes that contribute to human development and whose absence results in this syndrome, we have utilised a series of landmark cosmids to characterise a collection of WHS patient derived cell lines. Fluorescence in situ hybridisation with these cosmids was used to refine the WHS critical region (WHSCR) to 260 kb. The genomic sequence of this region is available and analysis of this sequence through BLAST detected several cDNA clones in the dbEST data base. A total of nine independent cDNAs, and their predicted translation products, from this analysis show no significant similarity to members of DNA or protein databases. Furthermore, these genes have been localised within the WHS critical region and reveal an interesting pattern of transcriptional organisation. A previously published report of a patient with proximal 4p- syndrome further refines the WHSCR to 165 kb defined by the loci D4S166 and D4S3327. This work provides the starting point to understand how multiple genes or other mechanisms can contribute to the complex phenotype associated with the Wolf-Hirschhorn syndrome.

Effect of the size of the deletion and clinical manifestation in Wolf-Hirschhorn syndrome: analysis of 13 patients with a de novo deletion

“…40,41 However, in more recent papers, where the deletions have been characterised with molecular methods, clinical data were not described in detail and photographs were lacking, which adds to a controversial debate if the variability of the clinical spectrum seen in WHS is reflected by the size of the deletion. 6,42 We correlated the clinical findings with the size of the deletion and came to the following conclusions: cleft lip/ palate, preauricular pits/tags, and colobomata were missing in patients with deletions smaller than 9 Mb and congenital heart defects were absent in patients with deletions smaller than 16 Mb. These conclusions are supported by other reported patients with small deletions, who lacked these clinical findings, eg the patients of Albiez et al, 43 Gandelmann et al, 42 and Johnson et al 40 Johnson et al 14 hypothesised that cardiac and lip and palatal defects are due to deletions located more proximally.…”

“…6 Interstitial deletions of 4p proximal to 4p16, cause a phenotype distinct from WHS. [35][36][37] Different mechanisms cause the deletion responsible in WHS: de novo simple deletions, unbalanced translocations due to familial translocations, or de novo complex chromosomal rearrangements such as unbalanced translocations result in 4p deletions.…”

“…[3][4][5] The minimal critical region has been narrowed down to 165 kb in the chromosomal band 4p16.3. 6 Potential candidate genes such as WHSC1, WHSC2, and LETM1 have been identified. [7][8][9] Although multiorganic expression corresponds well with affected organs in WHS, a direct link between these candidate genes and the broad clinical spectrum is missing.…”

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

“…11 Between B1.8 and 2.0 Mb from the 4p terminus, two adjacent critical regions were proposed based on the smallest region of overlap (SRO) among the deletions of individuals with or without the core features of WHS. The more proximal critical region (WHSCR) was delineated first 15 and mapping within this 165-kb interval identified two genes, WHSC1 and WHSC2. 16,17 The identification of two WHS patients with more distal 4p16.3 terminal deletion breakpoints 9,10 shifted and expanded the critical region (WHSCR-2) to a 300-600-kb region overlapping the 5 0 end of WHSC1 and encompassing LETM1, a candidate gene for seizures.…”

Wolf-Hirschhorn Syndrome (WHS) – Literature Review on the Features of the Syndrome

“…The genetics were not well developed at that moment, so no sooner than when Lejeune et al described the cri du chat syndrome as a partial deletion of chromosome 5, that it turned out the patient described by Hirschhorn and Cooper was characterized with other symptoms [1][2][3][4][5]. The vast majority of cases are caused by a deletion of 4p16.3 regio, especially among Wolf-Hirschhorn candidate genes or, so called, critical regions (WHSC1 and WHSC2) [1,3,6]. Small deletions are easier to diagnose than distal deletions [1].…”