title: Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome.
abstract: Sensenbrenner syndrome/cranioectodermal dysplasia (CED) is an autosomal-recessive disease that is characterized by craniosynostosis and ectodermal and skeletal abnormalities. We sequenced the exomes of two unrelated CED patients and identified compound heterozygous mutations in WDR35 as the cause of the disease in each of the two patients independently, showing that it is possible to find the causative gene by sequencing the exome of a single sporadic patient. With RT-PCR, we demonstrate that a splice-site mutation in exon 2 of WDR35 alters splicing of RNA on the affected allele, introducing a premature stop codon. WDR35 is homologous to TULP4 (from the Tubby superfamily) and has previously been characterized as an intraflagellar transport component, confirming that Sensenbrenner syndrome is a ciliary disorder.
authors.affiliation: Department of Human Genetics, Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Heleen H
authors.initials: HH
authors.lastname: Arts
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Spruijt
authors.forename: Dorus A
authors.initials: DA
authors.lastname: Mans
authors.forename: Peer
authors.initials: P
authors.lastname: Arts
authors.forename: Bart
authors.initials: B
authors.lastname: van Lier
authors.forename: Marloes
authors.initials: M
authors.lastname: Steehouwer
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Reeuwijk
authors.forename: Sarina G
authors.initials: SG
authors.lastname: Kant
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D004476:Ectodermal Dysplasia / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D013577:Syndrome
chemical_list: D051017:Apoptosis Regulatory Proteins; D008565:Membrane Proteins; D022821:RNA Splice Sites; C548806:naofen protein, human
references.citation: Nature. 2009 Sep 10;461(7261):272-6
references.pmid: 19684571
references.citation: Dev Dyn. 2009 May;238(5):1140-9
references.pmid: 19334287
references.citation: Am J Med Genet C Semin Med Genet. 2009 Nov 15;151C(4):281-95
references.pmid: 19876933
references.citation: Nat Genet. 2006 Sep;38(9):961-2
references.pmid: 16940995
references.citation: Am J Med Genet. 1997 Jun 27;70(4):349-52
references.pmid: 9182772
references.citation: Nature. 2008 Nov 6;456(7218):60-5
references.pmid: 18987735
references.citation: Nat Genet. 2007 Jun;39(6):727-9
references.pmid: 17468754
references.citation: Nat Genet. 2010 Jun;42(6):483-5
references.pmid: 20436468
references.citation: Neuroreport. 1995 Apr 19;6(6):845-9
references.pmid: 7612867
references.citation: Nat Biotechnol. 2009 Sep;27(9):847-50
references.pmid: 19668243
references.citation: Genome Res. 2010 Jan;20(1):110-21
references.pmid: 19858363
references.citation: J Pediatr. 1977 Jan;90(1):55-61
references.pmid: 830894
references.citation: Cell. 2004 May 14;117(4):527-39
references.pmid: 15137945
references.citation: Traffic. 2003 Jul;4(7):435-42
references.pmid: 12795688
references.citation: Am J Med Genet C Semin Med Genet. 2009 Nov 15;151C(4):263-80
references.pmid: 19876935
references.citation: Am J Hum Genet. 2010 Aug 13;87(2):282-8
references.pmid: 20673864
references.citation: Hum Mol Genet. 2009 May 15;18(10):1740-54
references.pmid: 19286674
references.citation: Am J Hum Genet. 2010 Jun 11;86(6):949-56
references.pmid: 20493458
references.citation: Nucleic Acids Res. 2002 Sep 1;30(17):3894-900
references.pmid: 12202775
references.citation: Hum Mol Genet. 2000 Jan 22;9(2):155-63
references.pmid: 10607826
references.citation: Am J Hum Genet. 2009 May;84(5):706-11
references.pmid: 19442771
references.citation: J Hered. 1990 Nov-Dec;81(6):424-7
references.pmid: 2250094
references.citation: Birth Defects Orig Artic Ser. 1975;11(2):372-9
references.pmid: 1227553