title: Mutations in NOTCH1 cause Adams-Oliver syndrome.
abstract: Notch signaling determines and reinforces cell fate in bilaterally symmetric multicellular eukaryotes. Despite the involvement of Notch in many key developmental systems, human mutations in Notch signaling components have mainly been described in disorders with vascular and bone effects. Here, we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects. Using whole-genome sequencing in a cohort of 11 families lacking mutations in the four genes with known roles in AOS pathology (ARHGAP31, RBPJ, DOCK6, and EOGT), we found a heterozygous de novo 85 kb deletion spanning the NOTCH1 5' region and three coding variants (c.1285T>C [p.Cys429Arg], c.4487G>A [p.Cys1496Tyr], and c.5965G>A [p.Asp1989Asn]), two of which are de novo, in four unrelated probands. In a fifth family, we identified a heterozygous canonical splice-site variant (c.743-1 G>T) in an affected father and daughter. These variants were not present in 5,077 in-house control genomes or in public databases. In keeping with the prominent developmental role described for Notch1 in mouse vasculature, we observed cardiac and multiple vascular defects in four of the five families. We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS. Our results suggest that mutations in NOTCH1 are the most common cause of AOS and add to a growing list of human diseases that have a vascular and/or bony component and are caused by alterations in the Notch signaling pathway.
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, USA.
authors.forename: Anna-Barbara
authors.initials: AB
authors.lastname: Stittrich
authors.affiliation: Department of Medical Genetics and Child and Family Research Institute, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Lehman
authors.affiliation: Inova Translational Medicine Institute, Inova Health System, Falls Church, VA 22042, USA.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Bodian
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Ashworth
authors.affiliation: Department of Medical Genetics and Child and Family Research Institute, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
authors.forename: Zheyuan
authors.initials: Z
authors.lastname: Zong
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Medical Genetics and Child and Family Research Institute, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lam
authors.affiliation: Inova Translational Medicine Institute, Inova Health System, Falls Church, VA 22042, USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Khromykh
authors.affiliation: Inova Translational Medicine Institute, Inova Health System, Falls Church, VA 22042, USA.
authors.forename: Ramaswamy K
authors.initials: RK
authors.lastname: Iyer
authors.affiliation: Inova Translational Medicine Institute, Inova Health System, Falls Church, VA 22042, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Vockley
authors.affiliation: Fairfax Neonatal Associates, Inova Health System, Falls Church, VA 22042, USA.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Baveja
authors.affiliation: Pediatric Gastroenterology Service, Centro Hospitalar do Porto, Porto 4050-111, Portugal.
authors.forename: Ermelinda Santos
authors.initials: ES
authors.lastname: Silva
authors.affiliation: Genetic Services, Wellington Hospital, Capital & Coast District Health Board, Wellington 6242, New Zealand.
authors.forename: Joanne
authors.initials: J
authors.lastname: Dixon
authors.affiliation: Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Eyby L
authors.initials: EL
authors.lastname: Leon
authors.affiliation: Inova Translational Medicine Institute, Inova Health System, Falls Church, VA 22042, USA; Department of Pediatrics, Inova Children's Hospital, Inova Health System, Falls Church, VA 22042, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Solomon
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Glusman
authors.affiliation: Inova Translational Medicine Institute, Inova Health System, Falls Church, VA 22042, USA. Electronic address: john.niederhuber@inova.org.
authors.forename: John E
authors.initials: JE
authors.lastname: Niederhuber
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, USA.
authors.forename: Jared C
authors.initials: JC
authors.lastname: Roach
authors.affiliation: Department of Medical Genetics and Child and Family Research Institute, University of British Columbia, Vancouver, BC V6H 3N1, Canada. Electronic address: mpatel@cw.bc.ca.
authors.forename: Millan S
authors.initials: MS
authors.lastname: Patel
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000818:Animals; D002675:Child, Preschool; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D007223:Infant; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D051881:Receptor, Notch1 / Q000235:genetics*; D012536:Scalp Dermatoses / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D055815:Young Adult
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1