(CAG)_n loci as genetic modifiers of age at onset in patients with spinocerebellar ataxia type 1 from mainland China

Abstract

Background and purpose The expanded repeat length in ATXN1 negatively correlates with age at onset (AAO) of spinocerebellar ataxia type 1 (SCA1) but can explain only part of it, indicating that other factors affect AAO. Some studies have explored the influence of non‐causative CAG repeats on the AAO of SCA patients. However, studies on Chinese SCA1 patients regarding candidate modifier factors involved in the variability in AAO are rare. Methods In all, 152 Chinese SCA1 patients who were genotyped for ATXN1 and nine other (CAG)n‐containing genes were enrolled. Regression analysis was performed to determine the effect of the expanded allele of ATXN1 (linear and quadratic effects) on AAO. Then, different models were used to explore the modulatory effect of nine other (CAG)n‐containing genes. Results Our results verified the negative effect of the expanded allele in ATXN1 by regression analysis. Some (CAG)n‐containing genes including TBP, ATN1 and HTT modified AAO with variance ranging from 0.8% to 3.8% and tended to decrease or delay AAO. However, no modifier effects of ATXN2, ATXN3, CACNA1A, ATXN7, KCNN3, RAI1 and normal ATXN1 alleles in trans were detected. Conclusion By using interaction analyses, TBP, ATN1 and HTT were determined to have modifying effects. Our study revealed that differences in modulation may be due to ethnic and geographic diversity across different populations. Furthermore, the variability of AAO was not completely explained by the genetic modifiers examined here, suggesting that other genetic or environmental factors are involved in these diseases.

Explainable artificial intelligence based on feature optimization for age at onset prediction of spinocerebellar ataxia type 3

“…The best feature optimization method (Crossing-Correlation-StepSVM) can improve the performance of different ML methods. For future research, the feature optimization method can be used for other polyQ diseases because the relationships between the AAO and genetic modifiers are similar in polyQ diseases, such as SCA1 (Wang et al, 2019 ), SCA2 (Hayes et al, 2000 ; Li et al, 2021 ), and HD (Hmida-Ben Brahim et al, 2014 ).…”

“…The CAG repeat length of the expanded ATXN3 is the major AAO factor of SCA3/MJD, but other polyQ-related genes ( CACNA1A, TBP, KCN3, RAI1, HTT, ATN 1, ATXN1, 2 , and 7 ) and gene interactions also have modifying effects on the AAO (Andresen et al, 2007 ; Tezenas Du Montcel et al, 2014 ; Chen et al, 2016a ). Other polyQ diseases, such as SCA1 (Wang et al, 2019 ), SCA2 (Hayes et al, 2000 ; Li et al, 2021 ), HD (Hmida-Ben Brahim et al, 2014 ), also have similar relationships.…”

The prevalence of type 1 spinocerebellar ataxia in Yakutia: current status

“…Сравнение средних значений числа повторов в указанных подгруппах с помощью однофакторного дисперсионного анализа показало их статистически значимые различия (p=0,000). При этом следует отметить, что число CAG повторов мутантного аллеля гена СЦА1 является основной характеристикой данной патологии, определяющей возраст манифестации и клиническую тяжесть заболевания [3].…”

Genetic and clinical profiles in a large cohort of Chinese individuals with spinocerebellar ataxia type 1

“…However, such descriptions were very rare, and only two studies with respectively 12 and 10 participants were reported [9,10]. The cohort of Wang et al was relatively large, but no clinical pro le except for AAO was analyzed [11].…”