title: Unmasking of a hemizygous WFS1 gene mutation by a chromosome 4p deletion of 8.3 Mb in a patient with Wolf-Hirschhorn syndrome.
abstract: The Wolf-Hirschhorn syndrome (WHS (MIM 194190)), which is characterized by growth delay, mental retardation, epilepsy, facial dysmorphisms, and midline fusion defects, shows extensive phenotypic variability. Several of the proposed mutational and epigenetic mechanisms in this and other chromosomal deletion syndromes fail to explain the observed phenotypic variability. To explain the complex phenotype of a patient with WHS and features reminiscent of Wolfram syndrome (WFS (MIM 222300)), we performed extensive clinical evaluation and classical and molecular cytogenetic (GTG banding, FISH and array-CGH) and WFS1 gene mutation analyses. We detected an 8.3 Mb terminal deletion and an adjacent 2.6 Mb inverted duplication in the short arm of chromosome 4, which encompasses a gene associated with WFS (WFS1). In addition, a nonsense mutation in exon 8 of the WFS1 gene was found on the structurally normal chromosome 4. The combination of the 4p deletion with the WFS1 point mutation explains the complex phenotype presented by our patient. This case further illustrates that unmasking of hemizygous recessive mutations by chromosomal deletions represents an additional explanation for the phenotypic variability observed in chromosomal deletion disorders.
authors.affiliation: Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands. k.tenberg@umcutrecht.nl
authors.forename: Klara
authors.initials: K
authors.lastname: Flipsen-ten Berg
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Hasselt
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Eleveld
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: van der Wijst
authors.forename: Frans A
authors.initials: FA
authors.lastname: Hol
authors.forename: Monique A M
authors.initials: MA
authors.lastname: de Vroede
authors.forename: Frits A
authors.initials: FA
authors.lastname: Beemer
authors.forename: P F Ron
authors.initials: PF
authors.lastname: Hochstenbach
authors.forename: Martin
authors.initials: M
authors.lastname: Poot
mesh_terms: D002675:Child, Preschool; D002872:Chromosome Deletion; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D054877:Wolf-Hirschhorn Syndrome / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D008565:Membrane Proteins; C114987:wolframin protein