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Higher genetic threshold for progressive adolescent idiopathic scoliosis in male individuals: commentary on an article by Lisa M. Kruse, MD, et al.: "Polygenic threshold model with sex dimorphism in adolescent idiopathic scoliosis: the Carter effect".

Adolescent idiopathic scoliosis (AIS) affects up to 3% of children worldwide. It has been known for many decades that the female-to-male ratio is about 2:1 for minor curves whereas the ratio increases with increasing curve severity, reaching about 10:1 for curves of >30°. The molecular mechanisms that account for the predominance of females in the progressive and severe forms of AIS are currently unknown. Kruse et al. provide results of their quantitative genetic analyses of families with AIS that support a polygenic threshold model with sex dimorphism.

Before commenting on the accompanying paper, there is a need to consider gene-variant effect sizes and the modes of inheritance of musculoskeletal and other disorders. In the past decade, rapid advances in genetic information and technology have enabled many new disease-associated genes to be identified in patients with skeletal dysplasias of unknown cause. The skeletal dysplasias include many hundreds of traits that usually follow Mendelian patterns of inheritance of single-gene disorders. In such traits, the gene-variant effect sizes are often large. Many studies have shown that very severe and lethal phenotypes, including those involving scoliosis, are often associated with very large single-gene-variant effect sizes. In such children, the adverse effects of the single gene mutations overwhelm any potentially beneficial effects of protective gene variants and environmental factors. However, families with milder Mendelian traits often have smaller single-gene-variant effect sizes and more marked variation in phenotypic severity. It is likely that the variation in severity of the phenotypes in such families is determined, at least in part, by the influence of other positive and negative gene variants and environmental factors. …