title: A syndromic form of Pierre Robin sequence is caused by 5q23 deletions encompassing FBN2 and PHAX.
abstract: Pierre Robin sequence (PRS) is an aetiologically distinct subgroup of cleft palate. We aimed to define the critical genomic interval from five different 5q22-5q31 deletions associated with PRS or PRS-associated features and assess each gene within the region as a candidate for the PRS component of the phenotype. Clinical array-based comparative genome hybridisation (aCGH) data were used to define a 2.08 Mb minimum region of overlap among four de novo deletions and one mother-son inherited deletion associated with at least one component of PRS. Commonly associated anomalies were talipes equinovarus (TEV), finger contractures and crumpled ear helices. Expression analysis of the orthologous genes within the PRS critical region in embryonic mice showed that the strongest candidate genes were FBN2 and PHAX. Targeted aCGH of the critical region and sequencing of these genes in a cohort of 25 PRS patients revealed no plausible disease-causing mutations. In conclusion, deletion of ∼2 Mb on 5q23 region causes a clinically recognisable subtype of PRS. Haploinsufficiency for FBN2 accounts for the digital and auricular features. A possible critical region for TEV is distinct and telomeric to the PRS region. The molecular basis of PRS in these cases remains undetermined but haploinsufficiency for PHAX is a plausible mechanism.
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Morad
authors.initials: M
authors.lastname: Ansari
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Rainger
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; Southeast Scotland Clinical Genetics Services, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Jennie E
authors.initials: JE
authors.lastname: Murray
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Hanson
authors.affiliation: DECIPHER, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Helen V
authors.initials: HV
authors.lastname: Firth
authors.affiliation: Cleft Lip and Palate Service, Royal Hospital for Sick Children, Edinburgh EH9 1LF, UK.
authors.forename: Felicity
authors.initials: F
authors.lastname: Mehendale
authors.affiliation: INSERM U-1163 Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, APHP, Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.affiliation: INSERM U-1163 Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, APHP, Paris, France.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Gordon
authors.affiliation: Departments of Medical Genetics and Pediatrics, University Hospital of Modena, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Percesepe
authors.affiliation: Department of Pediatrics, University of Bologna, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzanti
authors.affiliation: Department of Clinical Genetics, Alder Hey Children's Hospital, Liverpool L12 2AP, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Fryer
authors.affiliation: Departments of Medical Genetics and Pediatrics, University Hospital of Modena, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ferrari
authors.affiliation: Centre for Human Genetics, University of Leuven, Belgium.
authors.forename: Koenraad
authors.initials: K
authors.lastname: Devriendt
authors.affiliation: Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton and Wessex Clinical Genetics Service, University Hospital NHS Trust, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, UK.
authors.forename: I Karen
authors.initials: IK
authors.lastname: Temple
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; Southeast Scotland Clinical Genetics Services, Western General Hospital, Edinburgh EH4 2XU, UK. Electronic address: david.fitzpatrick@igmm.ed.ac.uk.
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
mesh_terms: D000293:Adolescent; D002648:Child; D002895:Chromosomes, Human, Pair 5; D002972:Cleft Palate / Q000235:genetics; D003025:Clubfoot / Q000150:complications; D003286:Contracture / Q000151:congenital; D004431:Ear, External / Q000002:abnormalities; D005260:Female; D000071840:Fibrillin-2; D000071837:Fibrillins; D005385:Fingers; D017353:Gene Deletion; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D020125:Mutation, Missense; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics*; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D010855:Pierre Robin Syndrome / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D013577:Syndrome; D055815:Young Adult
chemical_list: C000605723:FBN2 protein, human; C000605728:Fbn2 protein, mouse; D000071840:Fibrillin-2; D000071837:Fibrillins; D008840:Microfilament Proteins; D029543:Nucleocytoplasmic Transport Proteins; C498688:PHAX protein, human; D010750:Phosphoproteins
keywords: 5q deletion; Congenital contractural arachnodactyly; Fibrillin 2 (FBN2); Phosphorylated adaptor for RNA export (PHAX); Pierre Robin sequence; Talipes equinovarus