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 …

[1]  G. Gimelli,et al.  The same molecular mechanism at the maternal meiosis I produces mono- and dicentric 8p duplications. , 1996, American journal of human genetics.

[2]  H. Dörr,et al.  First known microdeletion within the Wolf-Hirschhorn syndrome critical region refines genotype-phenotype correlation. , 2001, American journal of medical genetics.

[3]  J. Stoye,et al.  REPuter: the manifold applications of repeat analysis on a genomic scale. , 2001, Nucleic acids research.

[4]  Dagmar Wieczorek,et al.  Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation. , 2002, American journal of human genetics.

[5]  V. P. Johnson,et al.  FISH detection of Wolf-Hirschhorn syndrome: exclusion of D4F26 as critical site. , 1994, American journal of medical genetics.

[6]  D. Wieczorek,et al.  Unexpected high frequency of de novo unbalanced translocations in patients with Wolf-Hirschhorn syndrome (WHS) , 2000, Journal of medical genetics.

[7]  J. Weber,et al.  Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. , 2001, American journal of human genetics.

[8]  Wilkie,et al.  Genetics of disease. , 1996, Current opinion in genetics & development.

[9]  Chad A Shaw,et al.  Development of a comparative genomic hybridization microarray and demonstration of its utility with 25 well-characterized 1p36 deletions. , 2003, Human molecular genetics.

[10]  J. Maier,et al.  Modulation of WHSC2 expression in human endothelial cells , 2000, FEBS letters.

[11]  B. Korf,et al.  Preliminary phenotypic map of chromosome 4p16 based on 4p deletions. , 1995, American journal of medical genetics.

[12]  A. Battaglia,et al.  Genotype-phenotype correlations and clinical diagnostic criteria in Wolf-Hirschhorn syndrome. , 2000, American journal of medical genetics.

[13]  E. Zackai,et al.  A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region. , 1997, Human molecular genetics.

[14]  P. Marynen,et al.  Delineation of the critical deletion region for congenital heart defects, on chromosome 8p23.1. , 1999, American journal of human genetics.

[15]  K. Devriendt,et al.  Wolf-Hirschhorn syndrome with cryptic 4p16.3 deletion and balanced/unbalanced mosaicism in the mother. , 1998, Annales de genetique.

[16]  N. Carter,et al.  DNA microarrays for comparative genomic hybridization based on DOP‐PCR amplification of BAC and PAC clones , 2003, Genes, chromosomes & cancer.

[17]  D. Ledbetter,et al.  An optimized set of human telomere clones for studying telomere integrity and architecture. , 2000, American journal of human genetics.

[18]  J. Veltman,et al.  Definition of a critical region on chromosome 18 for congenital aural atresia by arrayCGH. , 2003, American journal of human genetics.

[19]  A. Moorman,et al.  WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma. , 1998, Human molecular genetics.

[20]  P. Stankiewicz,et al.  Genome architecture, rearrangements and genomic disorders. , 2002, Trends in genetics : TIG.

[21]  G. Neri,et al.  Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. , 2003, American journal of human genetics.

[22]  Cécile Fizames,et al.  A comprehensive genetic map of the human genome based on 5,264 microsatellites , 1996, Nature.

[23]  J. Vermeesch,et al.  Mosaicism del(8p)/inv dup(8p) in a dysmorphic female infant: a mosaic formed by a meiotic error at the 8p OR gene and an independent terminal deletion event , 2003, Journal of medical genetics.

[24]  K. Devriendt,et al.  Chromosomal phenotypes and submicroscopic abnormalities , 2004, Human Genomics.

[25]  M. Altherr,et al.  Comparative analysis of a novel gene from the Wolf-Hirschhorn/Pitt-Rogers-Danks syndrome critical region. , 1999, Genomics.