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The Mutational Burden and Oligogenic Li et al. BMC Musculoskeletal Disorders (2020) 21:220 https://doi.org/10.1186/s12891-020-03229-x RESEARCH ARTICLE Open Access The mutational burden and oligogenic inheritance in Klippel-Feil syndrome Ziquan Li1,2,3, Sen Zhao1,2, Siyi Cai1, Yuanqiang Zhang1,2,3, Lianlei Wang1,2,3, Yuchen Niu2,4, Xiaoxin Li2,4, Jianhua Hu1, Jingdan Chen2, Shengru Wang1, Huizi Wang2, Gang Liu1,2, Ye Tian1, Zhihong Wu2,4, Terry Jianguo Zhang1,2,5, DISCO (Deciphering Disorders Involving Scoliosis and COmorbidities) study, Yipeng Wang1,2,5* and Nan Wu1,2,5* 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. Keywords: Klippel-Feil syndrome, Whole-exome sequencing, Genetic burden analysis, Genetic mutational spectrum, Oligogenic inheritance Background slight female predominance by approximately 3:2 [2, 3]. Klippel-Feil syndrome (KFS), which was first reported by However, the true incidence of KFS may be higher than Maurice Klippel and Andre Feil in 1912, is a complex skel- reported because of heterogeneity in phenotypic expres- etal disorder characterized by congenital fusion of two or sion and a lack of large-scale population screening studies. more cervical vertebrae [1]. The incidence of KFS has Based on retrospective studies of cervical computed tom- been estimated as approximately 1/40000–1/42000, with a ography (CT) in 2917 patients and 131 patients with cer- vical spondylotic myelopathy, the incidence of KFS may be as high as 1/172 to 5/131 [4, 5]. * Correspondence: [email protected]; [email protected] 1Department of Orthopedic Surgery, Peking Union Medical College Hospital, The main etiology of KFS is the impaired development Peking Union Medical College and Chinese Academy of Medical Sciences, of the cervical vertebrae, which leads to the improper seg- Beijing 100730, China mentation of the cervical spine. Although KFS can occur Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Li et al. BMC Musculoskeletal Disorders (2020) 21:220 Page 2 of 9 as an isolated malformation, it is often associated with a var- by the Department of Scientific Research and Ethics Com- iety of congenital diseases and other systemic malforma- mittee of PUMCH in China. tions, including scoliosis, Sprengel deformity, urinary malformations, gastrointestinal malformations, hearing im- Genomic DNA preparation and whole-exome sequencing pairment, congenital heart defects and various neurological Genomic DNA for 37 KFS patients (14 cases along with anomalies [1, 6–8]. In addition, congenital fusion deformity their healthy parents) was extracted from peripheral blood of the cervical vertebrae often alters the kinematics of the lymphocytes. WES was performed on peripheral blood cervical spine in ways that may accelerate degenerative DNA for all participants. DNA samples were prepared in changes throughout the region.Therefore,patientswith Illumina libraries and then underwent whole-exome cap- KFS usually complain of neck and back pain, respiratory ture with the SureSelect Human All Exon V6 + UTR r2 failure, and decreased mobility and may be at risk for death core design (91 Mb, Agilent, USA), followed by sequen- in severe cases due to a lack of early prediction methods. cing on the Illumina HiSeq 4000 platform in 150-bp Recent studies have suggested that the failed vertebral paired-end reads mode (Illumina, San Diego, CA, USA). segmentation underlying KFS is caused by defective somi- togenesis in the cervical region [9]. Autosomal dominant Variant annotation and interpretation and recessive inheritance patterns have both been reported WES data processing was performed with the in-house de- in families with KFS. According to Online Mendelian In- veloped PUMP (Peking Union Medical college hospital Pipe- heritance in Man (OMIM), mutations in GDF6 (MIM: line) [17]. Interpretation of single-nucleotide variants (SNVs) 601147), MEOX1 (MIM: 600147), GDF3 (MIM: 606522), and insertions/deletions (indel variant alleles) were adapted MYO18B (MIM: 607295) and RIPPLY2 (MIM: 609891) from the American College of Medical Genetics and Gen- have been associated with KFS [10–15]. Nevertheless, the omics (ACMG) guidelines [18]. Computational prediction basis of genetic predisposition to KFS is largely unknown tools(GenomicEvolutionaryRateProfiling[GERP][19], due to the rarity of the disease; only a small number of Combined Annotation Dependent Depletion [CADD] [20], KFS cases can be explained by the five specific pathogenic Sorting Intolerant Form Tolerant [SIFT] [21], Polyphen-2 genes mentioned above [16].Tofurtherdecipherthemo- [22], and MutationTaster [23]) were used to predict the con- lecular basis of KFS at the exome level, we herein investi- servation and pathogenicity of candidate variants. All vari- gate the molecular findings of WES among a cohort of 37 ants were compared to publicly available databases such as KFS patients/families, and further analyze rare variants by the 1000 Genomes Project (http://www.internationalgen- using a genetic burden method. ome.org/), the NHLBI GO Exome Sequencing Project (ESP) Exome Variant Server (http://evs.gs.washington.edu/EVS/), Methods and the Exome Aggregation Consortium (ExAC) database Cohort collection (http://exac.broadinstitute.org/). The in-house control data- From January 2016 to April 2018, we consecutively re- base consisted of WES data from 534 unrelated Chinese in- cruited 37 patients of Han Chinese ethnicity at Peking dividuals with no apparent skeletal anomalies from DISCO Union Medical College Hospital (PUMCH) who had been project. diagnosed with KFS under DISCO (Deciphering disorders Involving Scoliosis and COmorbidities, DISCO http://dis- Mutational burden analysis costudy.org/) project. Demographic information, physical A criterion of the internal (combined case and control examination results, clinical symptoms on presentation, population) and external (ExAC, and gnomAD) was used and a detailed medical history were obtained. Radiological to filter for rare genuine variants with a minor allele fre- assessments including anteroposterior, lateral neutral, and quency (MAF) < 0.001. flexion-extension plain radiographs; CT; and magnetic After filtering, we performed an initial analysis focusing on resonance imaging (MRI) were performed on each patient variants in reported pathogenic genes (GDF6, MEOX1, GDF3, to give a prior clinical diagnosis. Radiographic parameters MYO18B and RIPPLY2) related to KFS. Additionally, 96 genes of interest, such as the segmentation of congenitally fused that were biologically related to vertebral segmentation defects vertebrae, the Samartzis classification of KFS [8], cervical according to previous reports or the Human Phenotype scoliosis, and sagittal cervical alignment, were also re- Ontology (HPO; https://hpo.jax.org/), NCBI Gene (https:// corded. All radiographic evaluations were conducted by ncbi.nlm.nih.gov/gene/)andOMIM(http://omim.org/) data- trained spine surgeons, and the clinical review was per- bases were added to the candidate gene list (Table S1). formed by an alternate observer blinded to
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