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Open Access 01-12-2020 | Research article

The mutational burden and oligogenic inheritance in Klippel-Feil syndrome

Authors: Ziquan Li, Sen Zhao, Siyi Cai, Yuanqiang Zhang, Lianlei Wang, Yuchen Niu, Xiaoxin Li, Jianhua Hu, Jingdan Chen, Shengru Wang, Huizi Wang, Gang Liu, Ye Tian, Zhihong Wu, Terry Jianguo Zhang, Yipeng Wang, Nan Wu, DISCO (Deciphering Disorders Involving Scoliosis and COmorbidities) study

Published in: BMC Musculoskeletal Disorders | Issue 1/2020

Abstract

Background

Klippel-Feil syndrome (KFS) represents a rare anomaly characterized by congenital fusion of the cervical vertebrae. The underlying molecular etiology remains largely unknown because of the genetic and phenotypic heterogeneity.

Methods

We consecutively recruited a Chinese cohort of 37 patients with KFS. The clinical manifestations and radiological assessments were analyzed and whole-exome sequencing (WES) was performed. Additionally, rare variants in KFS cases and controls were compared using genetic burden analysis.

Results

We primarily examined rare variants in five reported genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of uncertain significance in MYO18B. Based on rare variant burden analysis of 96 candidate genes related to vertebral segmentation defects, we identified BAZ1B as having the highest probability of association with KFS, followed by FREM2, SUFU, VANGL1 and KMT2D. In addition, seven patients were proposed to show potential oligogenic inheritance involving more than one variants in candidate genes, the frequency of which was significantly higher than that in the in-house controls.

Conclusions

Our study presents an exome-sequenced cohort and identifies five novel genes potentially associated with KFS, extending the spectrum of known mutations contributing to this syndrome. Furthermore, the genetic burden analysis provides further evidence for potential oligogenic inheritance of KFS.

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Title: The mutational burden and oligogenic inheritance in Klippel-Feil syndrome
Authors: Ziquan Li
Sen Zhao
Siyi Cai
Yuanqiang Zhang
Lianlei Wang
Yuchen Niu
Xiaoxin Li
Jianhua Hu
Jingdan Chen
Shengru Wang
Huizi Wang
Gang Liu
Ye Tian
Zhihong Wu
Terry Jianguo Zhang
Yipeng Wang
Nan Wu
DISCO (Deciphering Disorders Involving Scoliosis and COmorbidities) study
Publication date: 01-12-2020
Publisher: BioMed Central
Published in: BMC Musculoskeletal Disorders / Issue 1/2020
Electronic ISSN: 1471-2474
DOI: https://doi.org/10.1186/s12891-020-03229-x

At a glance: The STEP trials

Springer Medicine

The mutational burden and oligogenic inheritance in Klippel-Feil syndrome

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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