title: Holoprosencephaly and preaxial polydactyly associated with a 1.24 Mb duplication encompassing FBXW11 at 5q35.1.
abstract: Holoprosencephaly (HPE) is the most common developmental defect affecting the forebrain and midface in humans. The aetiology of HPE is highly heterogeneous and includes both environmental and genetic factors. Here we report on a boy with mild mental retardation, lobar HPE, epilepsy, mild pyramidal syndrome of the legs, ventricular septal defect, vesicoureteral reflux, preaxial polydactyly, and facial dysmorphisms. Genome-wide tiling path resolution array based comparative genomic hybridisation (array CGH) revealed a de novo copy-number gain at 5q35.1 of 1.24 Mb. Additional multiplex ligation-dependent probe amplification screening of a cohort of 31 patients with HPE for copy-number changes at the 5q35.1 locus did not reveal any additional genomic anomalies. This report defines a novel 1.24 Mb critical interval for HPE and preaxial polydactyly at 5q35.1. The duplicated region encompasses seven genes: RANBP17, TLX3, NPM1, FGF18, FBXW11, STK10, and DC-UbP. Since FBXW11 is relatively highly expressed in fetal brain and is directly involved in proteolytic processing of GLI3, we propose FBXW11 as the most likely candidate gene for the HPE and prexial polydactyly phenotype. Additional research is needed to further establish the role of genes from the 5q35.1 region in brain and limb development and to determine the prevalence of copy number gain in the 5q35.1 region among HPE patients.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: David A
authors.initials: DA
authors.lastname: Koolen
authors.affiliation: Department of Clinical Genetics, Academic Hospital, Maastricht, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Herbergs
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Department of Neurology, St. Elisabeth and TweeSteden Hospital, Tilburg, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Stroink
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Sistermans
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Ad
authors.initials: A
authors.lastname: Geurts van Kessel
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 9101, 6500 HB, Nijmegen, The Netherlands. b.devries@antrg.umcn.nl.
authors.forename: Bert B A
authors.initials: BBA
authors.lastname: de Vries
mesh_terms: D000293:Adolescent; D000328:Adult; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D020440:Gene Duplication; D020131:Genes, Duplicate / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009693:Nucleic Acid Hybridization; D000090243:Nucleophosmin; D017689:Polydactyly / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics*
chemical_list: C471645:FBXW11 protein, human; C000716967:NPM1 protein, human; D044844:beta-Transducin Repeat-Containing Proteins; D000090243:Nucleophosmin; D044767:Ubiquitin-Protein Ligases