Genotype-phenotype correlation in 21 patients with Wolf-Hirschhorn syndrome using high-resolution array CGH

Nicole Maria C. Maas ¹, Griet Van Buggenhout ¹, Femke Hannes ¹, Bernard Thienpont ¹, Damien Sanlaville ², Klaas Kok ³, Alina Midro ⁴, Joris Andrieux ⁵, Britt-Marie Anderlid ⁶, Jacqueline Schoumans ⁶, Roel Hordijk ³, Koenraad Devriendt ¹, Jean-Pierre Fryns ¹ and Joris Vermeesch ^1*

¹ Centre for Human-Genetics, University of Leuven, Leuven, Belgium, Belgium
² Department Department of Genetics, Hôpital Necker-Enfants Malades, Assistance Publique-H&ocirc, France
³ Department of Medical Genetics, University Medical Center Groningen, Groningen, the Netherlands, Netherlands
⁴ Department of Clinical Genetics of the Medical University Bia³ystok, Poland, Poland
⁵ St Vincent Hospital, Lille, France, France
⁶ Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden, Sweden

^* To whom correspondence should be addressed. E-mail: joris.vermeesch{at}med.kuleuven.be.

Accepted 23 August 2007

Abstract

Introduction: The Wolf-Hirschhorn syndrome (WHS) is usually caused by terminal deletions of the short arm of chromosome 4 and is phenotypically defined by growth and mental retardation, seizures, and specific craniofacial manifestations. Large variation is observed in phenotypic expression of these features. In order to compare the phenotype with the genotype, we localized the breakpoints of the 4pter aberrations using a chromosome 4 specific tiling BAC/PAC array. Methods: In total, DNA from 21 patients was analyzed, of which 8 had a cytogenetic visible and 13 a submicroscopic deletion. Result and conclusion: In addition to classical terminal deletions sized between 1.9 and 30 Mb, we observed the smallest terminal deletion (1.4 Mb) ever reported in a patient with mild WHS stigmata. In addition, we identified and mapped interstitial deletions in four patients. This study positions the genes causing microcephaly, intrauterine and postnatal growth retardation between 0.3 and 1.4 Mb and further refines the regions causing CHD, CL/P, oligodontia, and hypospadias.

Keywords: WHS, chromosome 4, deletion, genotype-phenotype, tiling array CGH

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