The new Wolf–Hirschhorn syndrome critical region (WHSCR‐2): A description of a second case

Abstract

The Wolf-Hirschhorn syndrome (WHS), is a well known contiguous gene syndrome characterized by microcephaly, hypertelorism, prominent glabella, epicanthal folds, cleft lip or palate, cardiac defects, growth and mental retardation and seizures. The currently accepted WHS critical region (WHSCR) is localized between the loci D4S166 and D4S3327, where a deletion seems to generate all the clinical manifestations of the syndrome. Here we present a patient with a subtelomeric deletion of 4p16.3 showing growth and psychomotor delay with a typical WHS facial appearance and two episodes of seizures in conjunction with fever. The high-resolution G-banded karyotype was normal. Fluorescence in situ hybridization (FISH) with a set of cosmids from 4p16.3, showed that the deletion in this patient was from the D4S3327 to the telomere, enabling the size of the deletion to be estimated as 1.9 Mb, excluding the accepted WHSCR deletion. This patient supports the recent proposal by Zollino et al. [2003] that the critical region for WHS is located distally to the WHSCR between the loci D4S3327 and D4S98-D4S16, and it is called "WHSCR-2" [Zollino et al., 2003].

Phenocopy of Wolf–Hirschhorn syndrome in a patient with duplication 12q13.3q14.1

“…In addition, they considered additional key features likely due to haploinsufficiency of other genes in the region, representing true contiguous gene syndrome phenotypes. Support to the existence of the WHSCR2 was presented by Rodriguez et al [2005]. Thus, WHS appears as a distinct disorder characterized by a recognizable facial gestalt and clinical manifestations in which the phenotype is highly related to both the size and the location of deletions.…”

Wolf–Hirschhorn syndrome-associated chromosome changes are not mediated by olfactory receptor gene clusters nor by inversion polymorphism on 4p16

“…Red-red-green means presence of inversion (c). Fifty to hundred nuclei were analysed in individual subject patients except two (MG and patient 97), as previously reported (Zollino et al 2003;Rodriguez et al 2005).…”

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

“…Genotype-phenotype correlation studies have shown a relationship between deletion size and severity of clinical presentation. [6][7][8] Of patients meeting the minimal diagnostic criteria, 9 the smallest terminal deletion identified was B1.9 Mb, 1, 9,10 suggesting that genes within this interval of 4p16.3 are responsible for the core features of WHS. 8,11 Beyond this region, the loss of additional critical genes appears to be responsible for variably present features, such as congenital malformations or hearing loss.…”

“…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. 18 Although there is evidence to support a contribution of WHSC1 and LETM1 to the core WHS phenotype, 19,20 focal deletions or mutations of these genes have not been identified in WHS patients.…”