Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome.

TitleRare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome.
Publication TypeJournal Article
Year of Publication2015
AuthorsKaraca, E, Yuregir, OO, Bozdogan, ST, Aslan, H, Pehlivan, D, Jhangiani, SN, Akdemir, ZC, Gambin, T, Bayram, Y, Atik, MM, Erdin, S, Muzny, DM, Gibbs, RA, Lupski, JR
Corporate AuthorsBaylor-Hopkins Center for Mendelian Genomics
JournalAm J Med Genet A
Date Published2015 Nov
KeywordsAdolescent, Base Sequence, Female, Humans, Klippel-Feil Syndrome, Male, Molecular Sequence Data, Mutation, Pedigree, Radiography, Receptors, Notch, Signal Transduction, Spine

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.

Alternate JournalAm J Med Genet A
PubMed ID26238661
PubMed Central IDPMC4837953
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States

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