Dataset Information

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.

SUBMITTER: Karaca E

PROVIDER: S-EPMC4837953 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Karaca Ender E Yuregir Ozge O OO Bozdogan Sevcan T ST Aslan Huseyin H Pehlivan Davut D Jhangiani Shalini N SN Akdemir Zeynep C ZC Gambin Tomasz T Bayram Yavuz Y Atik Mehmed M MM Erdin Serkan S Muzny Donna D Gibbs Richard A RA Lupski James R JR

American journal of medical genetics. Part A 20150804 11

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 r ...[more]

PMID: 26238661

Similar Datasets

Project description:Importance:Children with Klippel-Feil syndrome (KFS), characterized principally by abnormal fusion of 2 or more cervical vertebrae, may have many additional congenital anomalies. The overall prevalence of otolaryngologic manifestations among patients with KFS has not been previously characterized. Objective:To define the otolaryngologic diagnoses made and procedures performed in 95 patients with KFS, which, to our knowledge, is the largest series of this challenging patient population published to date. Design, Setting, and Participants:For this retrospective review, all patients with KFS who underwent otolaryngology consultation at our institution over a 26-year period (January 1989 to December 2015) were included. Patients were identified using International Classification of Diseases, Ninth Revision (ICD-9) codes and were confirmed through individual medical record review. Relevant otolaryngologic diagnoses and procedures were extracted using ICD-9 and Current Procedural Terminology codes, respectively. Selected demographics included age, sex, number of clinic visits, and number of procedures. Main Outcomes and Measures:The primary outcomes were the otolaryngologic diagnoses and procedures associated with the KFS patient population; the secondary outcome was Cormack-Lehane classification documented during airway procedures. Results:Overall, 95 patients with KFS were included in this study (55 males [58%] and 40 females [42%]); mean (range) age at time of presentation to the otorhinolaryngology clinic was 5.8 (birth-23.0) years. Each patient with KFS averaged 8 visits to the otorhinolaryngology office and 5 otolaryngologic diagnoses. The most common diagnosis was conductive hearing loss (n?=?49 [52%]), followed by sensorineural hearing loss (n?=?38 [40%]), and dysphagia (n?=?37 [39%]). Sixty-two (65%) patients underwent otolaryngologic procedures, with 44 (46%) undergoing multiple procedures. The most common procedure was tympanostomy tube placement (n?=?36 [38%]), followed by office flexible endoscopy (n?=?23 [24%]). Twelve of the 20 patients who underwent direct laryngoscopy had documented Cormack-Lehane classification; 5 of 12 patients (42%) had a compromised view (grade 2, 3, or 4) of the larynx. Three patients required tracheotomies at this institution for airway stabilization purposes; each had severe upper airway obstruction leading to respiratory failure. Conclusions and Relevance:Patients with KFS require consultation for a variety of otolaryngologic conditions. Among these, hearing loss is the most common, but airway issues related to cervical spine fusion are the most challenging. Formulating an appropriate care plan in advance is paramount, even for routine otolaryngology procedures.

Project description:BackgroundKlippel-Feil syndrome (KFS) represents the rare and complex deformity characterized by congenital defects in the formation or segmentation of the cervical vertebrae. There is a wide gap in understanding the detailed mechanisms of KFS because of its rarity, heterogeneity, small pedigrees, and the broad spectrum of anomalies.MethodsWe recruited eight patients of Chinese Han ethnicity with KFS, five patients with congenital scoliosis (CS) who presented with congenital fusion of the thoracic or lumbar spine and without known syndrome or cervical deformity, and seven healthy controls. Proteomic analysis by data-independent acquisition (DIA) was performed to identify the differential proteome among the three matched groups and the data were analyzed by bioinformatics tools including Gene Ontology (GO) categories and Ingenuity Pathway Analysis (IPA) database, to explore differentially abundant proteins (DAPs) and canonical pathways involved in the pathogenesis of KFS.ResultsA total of 49 DAPs were detected between KFS patients and the controls, and moreover, 192 DAPs were identified between patients with KFS and patients with CS. Fifteen DAPs that were common in both comparisons were considered as candidate biomarkers for KFS, including membrane primary amine oxidase, noelin, galectin-3-binding protein, cadherin-5, glyceraldehyde-3-phosphate dehydrogenase, peroxiredoxin-1, CD109 antigen, and eight immunoglobulins. Furthermore, the same significant canonical pathways of LXR/RXR activation and FXR/RXR activation were observed in both comparisons. Seven of DAPs were apolipoproteins related to these pathways that are involved in lipid metabolism.ConclusionsThis study provides the first proteomic profile for understanding the pathogenesis and identifying predictive biomarkers of KFS. We detected 15 DAPs that were common in both comparisons as candidate predictive biomarkers of KFS. The lipid metabolism-related canonical pathways of LXR/RXR and FXR/RXR activation together with seven differentially abundant apolipoproteins may play significant roles in the etiology of KFS and provide possible pathogenesis correlation between KFS and CS.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets