Polygenic inheritance of adolescent idiopathic scoliosis: A study of extended families in Utah

Abstract

A heritability study of 69 extended Utah families with a history of adolescent idiopathic scoliosis (AIS) indicates that AIS is a polygenic, multifactorial condition. Each family reported a history of AIS within four generations; a total of 247 individuals were confirmed via X-rays and medical records to have AIS. Coefficient of kinship was more than 25 standard deviations higher for these 69 families than for the general population. Excluding all probands and assuming autosomal dominant inheritance, 1,260 individuals over the age of 16 were determined to be at risk for AIS because they have a parent with AIS. Assuming 50% of these individuals carry the allele, estimated penetrance in at-risk males is approximately 9%, and estimated penetrance in at-risk females is approximately 29%. Recurrence risk in relatives decreases as the degree of relationship to the affected individual becomes more distant; however, the lowest recurrence risk calculated, for third-degree relatives, is still an average of 9%, well above the general population's risk. Onset of AIS appears to be inherited separate from curve pattern and severity. In a study of phenotypes in 36 of the families, the affected individuals were consistent in either curve severity or curve pattern, but not both. It is unclear whether severity or pattern is more heritable, but it is possible that the location of the curve on the spine is the most heritable trait of the phenotype. The study demonstrates the genetic complexity of AIS, including the low penetrance of its cumulative alleles and variable expression.

Family history and its association to curve size and treatment in 1,463 patients with idiopathic scoliosis

“…When looking at the proportion of first-degree relatives having scoliosis, Wynne-Davies et al reported a prevalence of scoliosis in first-degree relatives of 6.9 % (10/144), Riszeborough et al 16 % (87/552) and Ward 24 % (372/1,513) [1][2][3]. We found a prevalence of scoliosis of 13 % (692/5,462) in first-degree relatives.…”

“…Wynne-Davies et al [1] reported that 27.2 % of the study participants were having at least one first-degree relative with scoliosis. In a cohort of 82 surgically treated patients, Ward et al [3] found a relative with scoliosis within four generations in 69 of the pedigrees (82 %). The relatively high proportion of patients with one or more relative with scoliosis (any kind) and the high prevalence of scoliosis among first-degree relatives in our study compared to some of the earlier studies may partly be a result of a selection bias.…”

“…When we looked at the sibling recurrent risk in our male study participants only, the prevalence of scoliosis in brothers was 10 % (12/114) and in sisters 15 % (20/134), with no significant difference compared to siblings to the female study participants. Ward et al [3] showed a large difference in sibling recurrent risk between brothers, 27 % (3/11), and sisters, 64 % (4.5/7), to male idiopathic scoliosis patients. However, this large difference should be interpreted cautiously due to the small number of study participants.…”

“…Relatives to patients with idiopathic scoliosis have a higher prevalence of scoliosis than the population in general, suggesting hereditary factors in the aetiology of this disorder [1][2][3]. This is supported by twin studies showing that the heritability of scoliosis is 38 % and that the concordance for scoliosis is higher in monozygotic than in dizygotic twin pairs [4][5][6][7].…”

An N‐Ethyl‐N‐Nitrosourea (ENU) Mutagenized Mouse Model for Autosomal Dominant Nonsyndromic Kyphoscoliosis Due to Vertebral Fusion

“…Indeed, the most common forms of kyphosis and scoliosis in adolescents are nonsyndromic and include: Scheuermann disease3 a form of nonsyndromic kyphosis, which affects >8% of the population12; idiopathic scoliosis (IS), which affects approximately 2% to 3% individuals13, 14, 15, 16; and congenital nonsyndromic scoliosis, which is reported to have a prevalence of approximately 0.5 to 1 per 1000 individuals 9. Familial and twin studies have indicated a genetic basis for kyphosis17, 18, 19, 20 and scoliosis,21, 22, 23, 24, 25, 26, 27, 28 with likely genetic heterogeneity. However, studies aimed at defining the genetic abnormalities causing these spinal disorders have been hampered by their phenotypic and genetic heterogeneity, variable modes of inheritance,8, 29 and gene‐environment interactions that may modify the phenotypic expression 9.…”