Identification of novel FBN1 variations implicated in congenital scoliosis.,Journal of Human Genetics

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Identification of novel FBN1 variations implicated in congenital scoliosis.
Journal of Human Genetics ( IF 2.6 ) Pub Date : 2019-12-11 , DOI: 10.1038/s10038-019-0698-x
Mao Lin _{1,

2,

3} , Sen Zhao _{1,

4} , Gang Liu _{1,

4} , Yingzhao Huang _{1,

4} , Chenxi Yu _{1,

2} , Yanxue Zhao ₁ , Lianlei Wang _{1,

2} , Yuanqiang Zhang _{1,

2} , Zihui Yan _{1,

2} , Shengru Wang ₁ , Sen Liu _{1,

4} , Jiaqi Liu _{4,

5} , Yongyu Ye ₆ , Yaping Chen ₁ , Xu Yang ₁ , Bingdu Tong ₁ , Zheng Wang _{3,

7} , Xinzhuang Yang ₈ , Yuchen Niu ₈ , Xiaoxin Li ₈ , Yipeng Wang _{1,

4,

9} , Jianzhong Su ₁₀ , Jian Yuan ₁₀ , Hengqiang Zhao ₁₀ , Shuyang Zhang ₁₁ , Guixing Qiu _{1,

4,

9} , , Shiro Ikegawa ₃ , Jianguo Zhang _{1,

4,

9} , Zhihong Wu _{4,

8,

9} , Nan Wu _{1,

4,

9}

Affiliation

Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.
Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China.
Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, 108-8639, Japan.
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.
Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, #58 Zhongshan 2nd Road, Guangzhou, 510080, China.
Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
Medical Research Center & Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.
Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China.
School of Ophthalmology & Optometry and Eye Hospital, School of Biomedical Engineering, Institute of Biomedical Big Data, Wenzhou Medical University, 325027, Wenzhou, China.
Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing, 100730, China.

Congenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations. Genetic predisposition has been demonstrated in CS. We previously reported that TBX6 loss-of-function causes CS in a compound heterozygous model; however, this model can explain only 10% of CS. Many monogenic and polygenic CS genes remain to be elucidated. In this study, we analyzed exome sequencing (ES) data of 615 Chinese CS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) project. Cosegregation studies for 103 familial CS identified a novel heterozygous nonsense variant, c.2649G>A (p.Trp883Ter) in FBN1. The association between FBN1 and CS was then analyzed by extracting FBN1 variants from ES data of 574 sporadic CS and 828 controls; 30 novel variants were identified and prioritized for further analyses. A mutational burden test showed that the deleterious FBN1 variants were significantly enriched in CS subjects (OR = 3.9, P = 0.03 by Fisher's exact test). One missense variant, c.2613A>C (p.Leu871Phe) was recurrent in two unrelated CS subjects, and in vitro functional experiments for the variant suggest that FBN1 may contribute to CS by upregulating the transforming growth factor beta (TGF-β) signaling. Our study expanded the phenotypic spectrum of FBN1, and provided nove insights into the genetic etiology of CS.

更新日期：2019-12-11

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