Segregation analysis of idiopathic scoliosis: Demonstration of a major gene effect

Axenovich, Tatiana I.; Зайдман, А. М.; Zorkoltseva, Irina V.; Tregubova, I.L.; Бородин, П. М.

doi:10.1002/(sici)1096-8628(19991008)86:4<389::aid-ajmg15>3.0.co;2-d

Cited by 83 publications

(35 citation statements)

References 36 publications

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“…Other studies have suggested a dominant genetic effect as a cause of idiopathic scoliosis [5]. Our findings do not support this since the models with an additive genetic effect provided a better fit in the variance partitioning than the models implying a dominant genetic effect.…”

Section: Discussioncontrasting

confidence: 99%

“…Relatives to patients with idiopathic scoliosis have a higher prevalence of this condition than the population in general, suggesting the importance of hereditary factors [1][2][3]. Pedigree studies and genetic analyses have so far shown inconsistent results both regarding the mode of heritability and possible genetic determinants associated with the scoliotic phenotype [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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Heritability of scoliosis

2011

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Purpose To estimate the heritability of scoliosis in the Swedish Twin Registry. Methods Self-reported data on scoliosis from 64,578 twins in the Swedish Twin Registry were analysed. Prevalence, pair-and probandwise concordances and tetrachoric correlations in mono-and dizygotic same-sex twins were calculated. The relative importance of genetic variance, i.e. the heritability, and unique and shared environmental variance was estimated using structural equation modelling in Mx software. In addition, all twins in the twin registry were matched against the Swedish Inpatient Register on the primary diagnosis idiopathic scoliosis. Results The prevalence of scoliosis was 4%. Pair-and probandwise concordance was 0.11/0.17 for mono-and 0.04/0.08 for same-sex dizygotic twins. The tetrachoric correlation (95% CI) was 0.41 (0.33-0.49) in mono-and 0.18 (0.09-0.29) in dizygotic twins. The most favourable model in the Mx analyses estimated the additive genetic effects (95% CI) to 0.38 (0.18-0.46) and the unique environmental effects to 0.62 (0.54-0.70). Shared environmental effects were not significant. The pairwise/ probandwise concordance for idiopathic scoliosis in the Swedish Inpatient Register was 0.08/0.15 for monozygotic and zero/zero for same-sex dizygotic twins. Conclusion Using self-reported data on scoliosis from the Swedish Twin Registry, we estimate that 38% of the variance in the liability to develop scoliosis is due to additive genetic effects and 62% to unique environmental effects. This is the first study of sufficient size to make heritability estimates of scoliosis.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heritability of scoliosis

2011

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“…Indeed, mild scoliosis or even mild curvature and/or rotation of the spine are likely to be caused by a combination of environmental and minor gene effects rather than by a major gene effect. 7 In addition, previous reports and our own observations showed that there are important variations in Cobb's angle measurements of up to 51 among different physicians. 18,19 This study shows the mapping of a new locus for dominant IS in a large family (F2) either on 5q13-q14 or on 3q11-q13.…”

Section: Discussionmentioning

confidence: 58%

“…A segregation analysis using a model with age and gender effects established a significant contribution of a major causal gene transmitted according to an autosomal dominant inheritance with sex-dependent incomplete penetrances. 7 A small number of model-dependent linkage analyses using an autosomal dominant model in large multigenerational IS families have been performed successfully to date. Indeed, such large multiplex IS families compatible with dominant inheritance are very rare.…”

Section: Introductionmentioning

confidence: 99%

New disease gene location and high genetic heterogeneity in idiopathic scoliosis

Edery

Margaritte‐Jeannin

Biot³

et al. 2011

Eur J Hum Genet

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International audienceIdiopathic scoliosis is a spine disorder of unknown origin with 1.5-3% prevalence in the general population. Besides the large multifactorial form sample of idiopathic scoliosis, 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 idiopathic scoliosis families compatible with dominant inheritance including 9 to 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 idiopathic scoliosis disease gene locus, since 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 idiopathic scoliosis 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 idiopathic scoliosis

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“…These studies also show a high genetic heterogeneity of either autosomal dominant inheritance with a major gene or multifactorial modes of inheritance. Autosomal dominant [3][4][5], X-linked dominant [6] and multifactorial inheritance [1,7,8] are commonly reported. In this study, we investigated 214 IS families recuited in Southwest Hospital (Chongqing, China) by using the genetic epidemiological method and analysed effects of genetic factors and the mode of inheritance through patients' age, IS incidence, familial aggregation and heritability, as well as traits of hereditary diseases.…”

Section: Introductionmentioning

confidence: 99%

Epidemiological survey of idiopathic scoliosis and sequence alignment analysis of multiple candidate genes

Yang

QuanZhang

Guo

et al. 2011

International Orthopaedics (SICOT)

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Purpose To investigate the effects of genetic factors on idiopathic scoliosis (IS) and genetic modes through genetic epidemiological survey on IS in Chongqing City, China, and to determine whether SH3GL1, GADD45B, and FGF22 in the chromosome 19p13.3 are the pathogenic genes of IS through genetic sequence analysis. Methods 214 nuclear families were investigated to analyse the age incidence, familial aggregation, and heritability. SH3GL1, GADD45B, and FGF22 were chosen as candidate genes for mutation screening in 56 IS patients of 214 families. The sequence alignment analysis was performed to determine mutations and predict the protein structure. Results The average age of onset of 10.8 years suggests that IS is a early onset disease. Incidences of IS in first-, second-, third-degree relatives and the overall incidence in families (5.68%) were also significantly higher than that of the general population (1.04%). The U test indicated a significant difference, suggesting that IS has a familial aggregation. The heritability of first-degree relatives (77.68 ±10.39%), seconddegree relatives (69.89 ±3.14%), and third-degree relatives (62.14 ±11.92%) illustrated that genetic factors play an important role in IS pathogenesis. The incidence of firstdegree relatives (10.01%), second-degree relatives (2.55%) and third-degree relatives (1.76%) illustrated that IS is not in simple accord with monogenic Mendel's law but manifests as traits of multifactorial hereditary diseases. Sequence alignment of exons of SH3GL1, GADD45B, and FGF22 showed 17 base mutations, of which 16 mutations do not induce open reading frame (ORF) shift or amino acid changes whereas one mutation (C→T)occurred in SH3GL1 results in formation of the termination codon, which induces variation of protein reading frame. Prediction analysis of protein sequence showed that the SH3GL1 mutant encoded a truncated protein, thus affecting the protein structure. Conclusion IS is a multifactorial genetic disease and SH3GL1 may be one of the pathogenic genes for IS.

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Segregation analysis of idiopathic scoliosis: Demonstration of a major gene effect

Cited by 83 publications

References 36 publications

Heritability of scoliosis

Heritability of scoliosis

New disease gene location and high genetic heterogeneity in idiopathic scoliosis

Epidemiological survey of idiopathic scoliosis and sequence alignment analysis of multiple candidate genes

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