title: Whole genome sequencing identifies ANXA3 and MTHFR mutations in a large family with an unknown equinus deformity associated genetic disorder.
abstract: The aim of this study was to characterize a previously uncharacterized genetic disorder associated with equinus deformity in a large Chinese family at the genetic level. Blood samples were obtained and whole genome sequencing was performed. Differential gene variants were identified and potential impacts on protein structure were predicted. Based on the control sample, several diseases associated variants were identified and selected for further validation. One of the potential variants identified was a ANXA3 gene [chr4, c.C820T(p.R274*)] variant. Further bioinformatic analysis showed that the observed mutation could lead to a three-dimensional conformational change. Moreover, a MTHFR variant that is different from variants associated with clubfoot was also identified. Bioinformatic analysis showed that this mutation could alter the protein binding region. These findings imply that this uncharacterized genetic disorder is not clubfoot, despite sharing some similar symptoms. Furthermore, specific CNV profiles were identified in association with the diseased samples, thus further speaking to the complexity of this multigenerational disorder. This study examined a previously uncharacterized genetic disorder appearing similar to clubfoot and yet having distinct features. Following whole genome sequencing and comparative analysis, several differential gene variants were identified to enable a further distinction from clubfoot. It is hoped that these findings will provide further insight into this disorder and other similar disorders.
authors.affiliation: Department of Orthopaedic, Nanjing Children's Hospital Affiliated to Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, Jiangsu, China.
authors.forename: Zhiqun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Internal Neurology, Nanjing Red Cross Hospital, Nanjing, 210001, Jiangsu, China.
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Kong
authors.affiliation: Nanjing Decode Genomics Biotechnology Co., Ltd., Nanjing, 210019, Jiangsu, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Nanjing Decode Genomics Biotechnology Co., Ltd., Nanjing, 210019, Jiangsu, China.
authors.forename: Wenxiang
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Orthopaedic, Nanjing Children's Hospital Affiliated to Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, Jiangsu, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ni
authors.affiliation: School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, 210096, Jiangsu, China. whitecf@seu.edu.cn.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Orthopaedic, Nanjing Children's Hospital Affiliated to Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, Jiangsu, China. yloucn@163.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lou
mesh_terms: D017318:Annexin A3 / Q000737:chemistry / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D001665:Binding Sites; D002681:China; D004863:Equinus Deformity / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D011487:Protein Conformation; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: C000614859:ANXA3 protein, human; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D017318:Annexin A3
keywords: ANXA3 gene; Inherited disease; Mutation; Whole genome sequencing