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.
Highlights
Congenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations potentially resulting from formation failure, segmentation defects, or a combination of both [1]
We identified a maternally inherited likely gene-disrupting (LGD) variant associated with the vertebral phenotypes in a family
We performed in vitro functional assay for a recurrent FBN1 variant (p.Leu871Phe) and revealed the upregulation of TGF-β signaling caused by the variant
Summary
Congenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations potentially resulting from formation failure, segmentation defects, or a combination of both [1]. We previously reported that a heterozygous 16p11.2 deletion or rare TBX6 loss-of-function (LoF) variants together with a common hypomorphic risk haplotype composed by three SNPs in trans cause CS [6]. We subsequently recapitulated this compound heterozygosity model in a gene-edited mouse [7], and defined the unique and clinically actionable phenotype of a monogenic form of CS, TBX6-associated CS (TACS) [8]. The subjects carrying highly deleterious FBN1 variants had vertebral malformations, malformations of the ribs, and intraspinal defects
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