Sequencing of the <i>TBX6</i> Gene in Families with Familial Idiopathic Scoliosis.

Abstract

A hypothesis-driven study was conducted in a familial cohort to determine the potential association between variants within the <i>TBX6</i> gene and Familial Idiopathic Scoliosis (FIS). To determine if variants within exons of the <i>TBX6</i> gene segregate with the FIS phenotype within a sample of families with FIS. Idiopathic Scoliosis (IS) is a structural curvature of the spine whose underlying genetic etiology has not been established. IS has been reported to occur at a higher rate than expected in family members of individuals with congenital scoliosis (CS), suggesting that the two diseases might have a shared etiology. The <i>TBX6</i> gene on chromosome 16p, essential to somite development, has been associated with CS in a Chinese population. Previous studies have identified linkage to this locus in families with FIS, and specifically with rs8060511, located in an intron of the <i>TBX6</i> gene. Parent-offspring trios from 11 families (13 trios, 42 individuals) with FIS were selected for Sanger sequencing of the <i>TBX6</i> gene. Trios were selected from a large population of families with FIS in which a genome-wide scan had resulted in linkage to 16p. Sequencing analyses of the subset of families resulted in the identification of five coding variants. Three of the five variants were novel; the remaining two variants were previously characterized and account for 90% of the observed variants in these trios. In all cases, there was no correlation between transmission of the <i>TBX6</i> variant allele and FIS phenotype. However, an analysis of regulatory markers in osteoblasts showed that rs8060511 is in a putative enhancer element. Although this study did not identify any <i>TBX6</i> coding variants that segregate with FIS, we identified a variant that is located in a potential <i>TBX6</i> enhancer element. Therefore, further investigation of the region is needed.