Scoliosis, Isolated, Susceptibility To, 1

Description

Idiopathic scoliosis is a structurally fixed lateral curvature of the spine with a rotatory component. There is at least a 10 degree curvature as demonstrated by upright spine roentgenograms by the Cobb method (Weinstein, 1994).

Scoliosis may occur secondary to other hereditary disorders including Marfan syndrome (154700), dysautonomia (223900), neurofibromatosis (see 162200), Friedreich ataxia (see 229300), and muscular dystrophies.

Genetic Heterogeneity of Susceptibility to Isolated Scoliosis

Loci for isolated scoliosis have been mapped to chromosome 19 (IS1), chromosome 17 (IS2; 607354), chromosome 8 (IS3; 608765), chromosome 9q31-q34 (IS4; 612238), and chromosome 17q25-qter (IS5; 612239).

Inheritance

De George and Fisher (1967) could not find evidence for operation of simple genetic factors for scoliosis. High concordance in both monozygotic and dizygotic twins and an excess of propositi born to older mothers suggested to these workers that maternal factors predominate.

Wynne-Davies (1968) favored either dominant or multifactorial inheritance. Dominant inheritance was suggested by Faber (1936), by Garland (1934) who observed the condition in 5 generations, and by Gilly et al. (1963).

Male-to-male transmission is apparently rare and was specifically absent in 17 families studied by Cowell et al. (1972), who suggested X-linked dominant inheritance. The 8 to 1 ratio of females to males supports this conclusion. Connor et al. (1987) did a systematic study of 87 families with early-onset scoliosis. Bell and Teebi (1995) described a French Canadian family in which a father and 2 daughters had idiopathic scoliosis. The parents were not known to be related.

Axenovich et al. (1999) performed segregation analysis on 101 pedigrees ascertained through a proband with idiopathic scoliosis, using a model with age and gender effects. When they analyzed the pedigrees defining affected status as persons with a Cobb angle of more than 5 degrees, they detected no significant major gene effect. However, when the affected status was assigned only to persons with pronounced forms of disease (a curve of at least 11 degrees), a significant contribution of a major causal gene could be established and inheritance could be described according to a dominant major gene diallele model, assuming incomplete sex- and age-dependent penetrance of genotypes.

Inoue et al. (1998) studied idiopathic scoliosis in 21 pairs of twins in whom DNA fingerprinting was used to establish monozygosity in 13 and dizygosity in 8. There was concordance for idiopathic scoliosis in 92.3% of monozygotic and 62.5% of dizygotic twins. Of the 12 pairs of monozygotic twins concordant for idiopathic scoliosis, 6 showed discordant curve patterns.

In a study of 69 extended Utah families with a history of adolescent idiopathic scoliosis, including a total of 247 affected individuals with disease confirmed by x-rays and medical records, Ward et al. (2010) concluded that the condition is polygenic and multifactorial. Excluding all probands and assuming autosomal dominant inheritance, 1,260 individuals over the age of 16 years were determined to be at risk because they had a parent with AIS. Assuming 50% of those individuals carried the allele, estimated penetrance in at-risk males was approximately 9%, whereas that for at-risk females was approximately 29%. The lowest recurrence risk calculated, for third-degree relatives, was still an average of 9%, well above the general population's risk. Onset of AIS appeared to be inherited separately from curve pattern and severity. In a study of phenotypes in 36 of the families, affected individuals were consistent in either curve severity or curve pattern, but not both. The authors stated that it was unclear whether severity or pattern was more heritable, but that the location of the curve on the spine might be the most heritable trait of the phenotype. Ward et al. (2010) concluded that AIS is genetically complex, with low penetrance of cumulative alleles and variable expression.

Mapping

Chan et al. (2002) studied 7 unrelated multiplex families of Chinese descent with adolescent idiopathic scoliosis, comprising 25 affected members, and performed a genomewide scan with more than 400 fluorescent microsatellite markers. Multipoint linkage analysis revealed significant linkage to the distal short arm of chromosome 19, with both a maximum multipoint lod score and a nonparametric lod score of 4.93. Two-point linkage analysis gave a lod score of 3.63 at a recombination fraction of 0.00 at D19S216. Refinement placed the locus in a region spanning 5.2 cM on the sex-averaged genetic map on 19p13.3.

Associations Pending Confirmation

In 5 families with at least 2 individuals with scoliosis, one of whom in each family had 'triple-curve' scoliosis, in which affected individuals had 3 distinct scoliotic curves that each measured at least 10 degrees, Marosy et al. (2010) performed genomewide linkage analysis and identified the most significant values for D6S1065 on chromosome 6q (p less than 2.0 x 10(-10)) and for D10S677 on chromosome 10q (p less than 5.0 x 10(-7)). Fine mapping with SNPs narrowed the loci to a 1.0-Mb interval on chromosome 6q and a 7.0-Mb interval on chromosome 10q (p less than 0.001).

Molecular Genetics

Associations Pending Confirmation

Ogura et al. (2015) performed a genomewide association study (GWAS) of 2,109 affected subjects with adolescent idiopathic scoliosis compared with 11,140 control subjects. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, Ogura et al. (2015) identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 x 10 (13), OR = 1.21, 95% CI 1.15-1.27). The most significantly associated SNPs were in intron 3 of BNC2 (608669), which encodes the zinc finger transcription factor basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs had the potential to regulate BNC2 transcription activity and that susceptibility alleles increased BNC2 expression. Ogura et al. (2015) identified a functional SNP, rs10738445, in BNC2 whose susceptibility allele showed both higher binding to a transcription factor, YY1 (600013), and higher BNC2 enhancer activity than the nonsusceptibility allele. Finally, Ogura et al. (2015) showed that BNC2 overexpression produced body curvature in developing zebrafish in a gene dosage-dependent manner. Ogura et al. (2015) concluded that increased BNC2 expression is implicated in the etiology of adolescent idiopathic scoliosis.

For discussion of a possible association between scoliosis and variation in the POC5 gene, see 617880.

Animal Model

Opsahl et al. (1984) showed an inverse relationship between the amount of copper in the diet and the severity and incidence of scoliosis in scoliosis-prone chickens.