Nancy Hadley Miller, MD
Familial idopathic scoliosis
Familial idiopathic scoliosis is a complex genetic disorder highly prevalent in the general population (2-3%) and with wide variability in presentation. When progressive, marked deformity and operative spinal fusion can result. An estimated 15-20,000 spinal fusions are performed in adolescents each year with an approximate cost of $1.4 billion. The goal of this research is to define the genes responsible for this disorder from a large, well-defined sample of families with at least two first degree relatives with scoliosis, in the hope that by understanding the causative meutation of this disorder improved therapeutic modalities can be developed.
Our laboratory focuses on the identification of genetic loci and mutations in genes responsible for familial idiopathic scoliosis. A genomic-wide scan of an identified study sample (202 families, 1208 individuals) was completed followed by linkage analyses These results have suggested primary and secondary candidate regions on multiple chromosomes with a potential significant relationship to the observed phenotype. To date, fine mapping efforts have verified areas on chromosomes 6, 9, and 16 and have narrowed the intervals to 4-8 centimorgans. Stratification of the sample by mode of inheritance and additional phenotypic criteria has resulted in areas on chromosomes X, 5, and 13 to be potentially significant within subgroups of families. Finemapping has again verified and narrowed these areas to 2.5 – 8 centimorgans.
To narrow further the critical regions, an approach utilizing high-density biallelic markers (SNPs) is being combined with locus-specific association studies. The chances of observing linkage disequilibrium with the disease alleles is markedly improved through the pooling of adjacent SNP loci and marker loci for statistical association studies. Candidate genes within several narrow regions have been scrutinized on the basis of the known biology of the encoded proteins, their homology to proteins of known function, and on the basis of a positive statistical linkage to the observed phenotype. The laboratory has incorporated new techniques and methodologies as they are developed and available, such as new custom developed microarrays of biallelic polymorphisms or SNPs.
The rationale of this effort is to be able to identify at-risk individuals prior to the onset of curvature. Secondarily, specific genetic groups of individuals may be stratified earlier into therapeutic protocols. This may allow for earlier limited surgical intervention and avoid long-term bracing which, in many cases, results in an extensive surgical intervention once initial treatment has failed.
Selected Publications
1. Characterization of Idiopathic Scoliosis in a Clinically Well-defined Population. Miller, N.H., Schwab, D., Sponseller, P.D., Manolio, T., Pugh, E., Wilson, A. Clin. Orthop. :392; 349-357, 2001
2. Genetic heterogeneity comprising both X-linked and autosomal dominant forms of inheritance in families with familial idiopathic scoliosis. Justice, C.M., Miller, N.H., Marosy, B., Zhang, J., Pugh, E.W., Wilson, A.F. Am Journal of Human Gen. Vol. 69 Sup.2, (4) 384, 2001
3.Identification of loci in familial idiopathic scoliosis. Miller, N.H., Justice, C.M., Marosy, B., Zhang, J., Wilson, A.F. Am Journal of Human Gen. Vol. 71(4):A1577, 2002
4.Familial idiopathic scoliosis: Evidence of an X-linked susceptibility. Miller, N.H., Justice, C.M., Marosy,B., Zhang, J., Wilson,A.F. Spine March 15;28(6):589-94 2003
5.Genetic Linkage of Kyphoscoliosis. Justice, C.M., Marosy, B., Novak, S., Boyce, P., Pettengill, J., Doheny, K., Pugh, E.W., Wilson, A.F., Miller, N.H. Am Journal of Human Gen. Vol. 73(5):A1744, 2003
6.Identification of Candidate Regions for Familial Idiopathic Scoliosis.
Miller, N.H., Justice,
C.M., Marosy, B., Doheny, K.F., Pugh, E., Zhang, J., Dietz, H.C., Wilson,
A.F., Spine, 30;10 :1181-1187, 2005
7.Lack of Association between the Aggrecan Gene and Familial Idiopathic Scoliosis. Marosy, B., Justice, C., Nzegwu, N., Kumar, G., Wilson, A. F., Miller, N.H. Spine, 31;13:1420-1425, 2006
8.Genetic Loci for Kyphoscoliosis on Chromosome 5p13, 13q13.3, and 13q32. Miller, N. H., Marosy, B., Justice, C., Novak, S., Tang, E., Boyce, O., Pettengil, J., Doheny, K., Pugh, E., Wilson, A.F. Am J Med Genet A, 140(10):1059-1068, 2006
9.Idiopathic scoliosis: identification of candidate regions on chromosome
19p13. Alden KJ,
Marosy B, Nzegwu N, Justice CM, Wilson AF, Miller NH: Spine 31(16):1815-1819,
2006
10.Genetic Association of Complex Traits: Using Idiopathic Scoliosis
as an Example. Cheng JC, Tang NL, Yeung HY, Miller NH., Clin Orthop Relat
Res, May 24, 2007.