New disease gene location and high genetic heterogeneity in idiopathic scoliosis

Abstract

Idiopathic scoliosis (IS) is a spine disorder of unknown origin with 1.5-3% prevalence in the general population. Besides the large multifactorial-form sample of IS, there is a good evidence for the existence of a monogenic subgroup in which the disease is inherited in a dominant manner. However, results from literature suggest a strong heterogeneity in the locations of the mutated genes. Using a high-resolution genome-wide scan, we performed linkage analyses in three large multigenerational IS families compatible with dominant inheritance including 9-12 affected members or obligate carriers. In two of these families, our results suggested intra-familial genetic heterogeneity, whereas, in the other, we observed a perfect marker disease co-segregation in two regions at 3q12.1 and 5q13.3. We can state that one of these two locations is a novel IS disease gene locus, as the probability of having this perfect co-segregation twice by chance in the genome is very low (P=0.001). Lastly, in all three families studied, linkage to the previously mapped dominant IS loci on chromosomes 19p13.3, 17p11.2, 9q34, 17q25 and 18q is unlikely, confirming that there is a high genetic heterogeneity within the subgroup of dominant forms of IS.