Abstract
Introduction
Idiopathic scoliosis (IS) has been associated with several genetic loci in varying study populations, reflecting the disorder's genetic complexity. One region of interest is on chromosome 17, flanking regions linked to neurofibromatosis type 1 (NF1). This region is of particular relevance because the most common osseous manifestation in NF1 is scoliosis (10–30% of patients). This alludes to a potential genetic correlation within this region affecting spinal development or stability. The objective of this research is to identify candidate genes within this region that are statistically linked to IS.
Methods
An initial population of IS families recruited through approval by the institutional review board (202 families; 1198 individuals) had DNA harvested from blood, and underwent genomic screening, finemapping, and statistical analyses. We identified a specific familial subset: families with males having undergone surgery for scoliosis (17 families, 147 individuals). The initial genome-wide scan indicated that this subset was linked to chromosome 17q.11.2. The most prominent marker, D17s975, (p=0·0003) at 25.12 Mb is adjacent to the NF1 deletional region. We then analysed a custom panel of single-nucleotide polymorphisms (SNPs) extending from 18·30–31·47 Mb for linkage through Taqman SNP assay protocol. With allele specific fluorescent tags, allelic discrimination was done with real-time PCR.
Results
Findings show two regions with two or more contiguous SNPs of significance (p<0·05), confirming significant linkage adjacent to the NF1 locus (table). The most significant results lie within the serotonin transporter gene SLC6A4, whose product is a modulator of serotonin (5-HT) activity.
Conclusions
IS is a disorder of variable phenotypic expression that has been related to several regions on the genome. Although NF1 has been definitively associated with a region on chromosome 17, the phenotypic expression is not understood at the molecular level. The elucidation of shared genetic variations within this region by two disorders marked by scoliosis has significance for the molecular understanding of the pathogenesis of scoliosis and axial development. The specific gene, SLC6A4, is of particular interest in that as a modulator of serotonin transport, bone mineral content, density, and mechanical strength can be altered. Both NF1 and IS in some patients have been associated with decreased bone mineral density. Future work will focus on replication of these findings and targeted genetic sequencing.
