Identification of Novel FBN1 Variations Implicated in Congenital Scoliosis

Overview

Journal J Hum Genet

Specialty Genetics

Date 2019 Dec 13

PMID 31827250

Citations 15

Authors

Mao Lin

Sen Zhao

Gang Liu

Yingzhao Huang

Chenxi Yu

Yanxue Zhao

Lianlei Wang

Yuanqiang Zhang

Zihui Yan

Shengru Wang

Sen Liu

Jiaqi Liu

Yongyu Ye

Yaping Chen

Xu Yang

Bingdu Tong

Zheng Wang

Xinzhuang Yang

Yuchen Niu

Xiaoxin Li

Yipeng Wang

Jianzhong Su

Jian Yuan

Hengqiang Zhao

Shuyang Zhang

Guixing Qiu

Shiro Ikegawa

Jianguo Zhang

Zhihong Wu

Nan Wu

Affiliations

Soon will be listed here.

Abstract

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.

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