title: Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies.
abstract: BACKGROUND
  Adams-Oliver syndrome (AOS) is a rare disorder characterized by congenital limb defects and scalp cutis aplasia. In a proportion of cases, notable cardiac involvement is also apparent. Despite recent advances in the understanding of the genetic basis of AOS, for the majority of affected subjects, the underlying molecular defect remains unresolved. This study aimed to identify novel genetic determinants of AOS.
  
  
  RESULTS
  Whole-exome sequencing was performed for 12 probands, each with a clinical diagnosis of AOS. Analyses led to the identification of novel heterozygous truncating NOTCH1 mutations (c.1649dupA and c.6049_6050delTC) in 2 kindreds in which AOS was segregating as an autosomal dominant trait. Screening a cohort of 52 unrelated AOS subjects, we detected 8 additional unique NOTCH1 mutations, including 3 de novo amino acid substitutions, all within the ligand-binding domain. Congenital heart anomalies were noted in 47% (8/17) of NOTCH1-positive probands and affected family members. In leukocyte-derived RNA from subjects harboring NOTCH1 extracellular domain mutations, we observed significant reduction of NOTCH1 expression, suggesting instability and degradation of mutant mRNA transcripts by the cellular machinery. Transient transfection of mutagenized NOTCH1 missense constructs also revealed significant reduction in gene expression. Mutant NOTCH1 expression was associated with downregulation of the Notch target genes HEY1 and HES1, indicating that NOTCH1-related AOS arises through dysregulation of the Notch signaling pathway.
  
  
  CONCLUSIONS
  These findings highlight a key role for NOTCH1 across a range of developmental anomalies that include cardiac defects and implicate NOTCH1 haploinsufficiency as a likely molecular mechanism for this group of disorders.
authors.affiliation: Division of Genetics & Molecular Medicine, King's College London, Faculty of Life Sciences & Medicine, Guy's Hospital, London, United Kingdom.|Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Southgate
authors.affiliation: Institute of Human Genetics, Otto-von-Guericke-Universität Magdeburg, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Sukalo
authors.affiliation: School of Life Sciences, University of Lincoln, Lincoln, United Kingdom.
authors.forename: Anastasios S V
authors.initials: ASV
authors.lastname: Karountzos
authors.affiliation: School of Life Sciences, University of Lincoln, Lincoln, United Kingdom.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Taylor
authors.affiliation: Division of Genetics & Molecular Medicine, King's College London, Faculty of Life Sciences & Medicine, Guy's Hospital, London, United Kingdom.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Collinson
authors.affiliation: Department of Clinical Genetics, Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
authors.forename: Deborah
authors.initials: D
authors.lastname: Ruddy
authors.affiliation: Department of Clinical Genetics, South West Thames Regional Genetics Service, St George's Healthcare NHS Trust, London, United Kingdom.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Snape
authors.affiliation: Scientific Directorate, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.affiliation: South West of Scotland Clinical Genetics Service, Southern General Hospital, Glasgow, United Kingdom.
authors.forename: John L
authors.initials: JL
authors.lastname: Tolmie
authors.affiliation: South West of Scotland Clinical Genetics Service, Southern General Hospital, Glasgow, United Kingdom.
authors.forename: Shelagh
authors.initials: S
authors.lastname: Joss
authors.affiliation: Department of Medical, Oral & Biotechnological Sciences, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.affiliation: Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Digilio
authors.affiliation: Ambulantes Gesundheitszentrum der Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Luitgard M
authors.initials: LM
authors.lastname: Graul-Neumann
authors.affiliation: Clinical Genetics Unit, Department of Woman & Child Health, University of Padova, Padova, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.affiliation: Institute of Human Genetics, Mainz University Medical Center, Mainz, Germany.
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Coerdt
authors.affiliation: Pediatric Hepatology & Liver Transplantation Unit, Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, Hepatinov, Le Kremlin Bicêtre, France.|Inserm U1174, University Paris-Sud 11, Orsay, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Jacquemin
authors.affiliation: Department of Medical Genetics, University & University Hospital of Antwerp, Edegem, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Wuyts
authors.affiliation: Institute of Human Genetics, Otto-von-Guericke-Universität Magdeburg, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.affiliation: School of Life Sciences, University of Lincoln, Lincoln, United Kingdom.
authors.forename: Rajiv D
authors.initials: RD
authors.lastname: Machado
authors.affiliation: Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom.|Department of Clinical Genetics, Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D004476:Ectodermal Dysplasia / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057895:Haploinsufficiency; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D010375:Pedigree; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000737:chemistry / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012536:Scalp Dermatoses / Q000151:congenital* / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult
chemical_list: D051881:Receptor, Notch1
keywords: Adams–Oliver syndrome; genetics; haploinsufficiency; heart defects, congenital; receptor, NOTCH1