title: Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome.
abstract: Klippel-Feil syndrome is a rare disorder represented by a subgroup of segmentation defects of the vertebrae and characterized by fusion of the cervical vertebrae, low posterior hairline, and short neck with limited motion. Both autosomal dominant and recessive inheritance patterns were reported in families with Klippel-Feil. Mutated genes for both dominant (GDF6 and GDF3) and recessive (MEOX1) forms of Klippel-Feil syndrome have been shown to be involved in somite development via transcription regulation and signaling pathways. Heterotaxy arises from defects in proteins that function in the development of left-right asymmetry of the developing embryo. We describe a consanguineous family with a male proband who presents with classical Klippel-Feil syndrome together with heterotaxy (situs inversus totalis). The present patient also had Sprengel's deformity, deformity of the sternum, and a solitary kidney. Using exome sequencing, we identified a homozygous frameshift mutation (c.299delT; p.L100fs) in RIPPLY2, a gene shown to play a crucial role in somitogenesis and participate in the Notch signaling pathway via negatively regulating Tbx6. Our data confirm RIPPLY2 as a novel gene for autosomal recessive Klippel-Feil syndrome, and in addition-from a mechanistic standpoint-suggest the possibility that mutations in RIPPLY2 could also lead to heterotaxy. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Ender
authors.initials: E
authors.lastname: Karaca
authors.affiliation: Department of Medical Genetics, Numune Training and Research Hospital, Adana, Turkey.
authors.forename: Ozge O
authors.initials: OO
authors.lastname: Yuregir
authors.affiliation: Department of Medical Genetics, Mersin University, Mersin, Turkey.
authors.forename: Sevcan T
authors.initials: ST
authors.lastname: Bozdogan
authors.affiliation: Department of Medical Genetics, Medical Faculty of Eskisehir Osmangazi University, Eskisehir, Turkey.
authors.forename: Huseyin
authors.initials: H
authors.lastname: Aslan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Zeynep C
authors.initials: ZC
authors.lastname: Akdemir
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Bayram
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Mehmed M
authors.initials: MM
authors.lastname: Atik
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Serkan
authors.initials: S
authors.lastname: Erdin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Texas Children's Hospital, Houston, Texas.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D005260:Female; D006801:Humans; D007714:Klippel-Feil Syndrome / Q000000981:diagnostic imaging / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011859:Radiography; D051880:Receptors, Notch / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D013131:Spine / Q000000981:diagnostic imaging
chemical_list: D051880:Receptors, Notch
keywords: Klippel-Feil syndrome; heterotaxy; notch signaling; right-left axis determination; somitogenesis