脊髓小脑共济失调 37 型的新基因型与表型相关性、小脑等位基因特异性甲基化差异以及 (ATTTC)n 插入的共同起源。

IF 3.8 2区 生物学 Q2 GENETICS & HEREDITY
Human Genetics Pub Date : 2024-03-01 Epub Date: 2024-02-23 DOI:10.1007/s00439-024-02644-7
Marina Sanchez-Flores, Marc Corral-Juan, Esther Gasch-Navalón, Davide Cirillo, Ivelisse Sanchez, Antoni Matilla-Dueñas
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引用次数: 0

摘要

脊髓小脑共济失调亚型 37(SCA37)是一种罕见疾病,最初是在伊比利亚半岛的共济失调患者中发现的一种纯粹的小脑综合征。SCA37患者携带一个致病性内含子(ATTTC)n重复插入,两侧是残疾-1(DAB1)基因中的两个多态性(ATTTT)n重复,导致小脑功能失调。在这里,我们通过CRISPR-Cas9和长线程纳米孔测序确定了致病性5'(ATTTT)n-(ATTTC)n-3'(ATTTT)n SCA37等位基因的精确结构,揭示了它们在SCA37淋巴细胞、成纤维细胞和小脑样本中的表观基因组特征,并建立了新的分子和临床相关性。5'(ATTTT)n-(ATTTC)n-3'(ATTTT)n致病等位基因配置显示了重复的不稳定性和不同的甲基化特征。发病年龄与(ATTTC)n呈负相关,与3'(ATTTT)n呈正相关。地理来源和性别与发病年龄明显相关。此外,通过机器学习,考虑性别、(ATTTC)n、3'(ATTTT)n 和 SCA37 小脑中差异甲基化的 7 个 CpG 位置,对发病年龄和疾病演变获得了重要的预测回归模型。在分析的葡萄牙和西班牙的所有 SCA37 患者中,发现了一个跨越 (ATTTC)n 插入的 964-kb 的共同基因组区域,证明 SCA37 突变的共同起源是在 859 年前的伊比利亚半岛(95% CI 647-1378)。总之,我们利用 CRISPR/Cas9 富集和纳米孔长读数测序技术,准确测定了调控性 5'(ATTTT)n-(ATTTC)n-3'(ATTTT)n 重复序列的大小和结构,避免了 PCR 偏差扩增,从而为 SCA37 的准确基因诊断提供了依据。此外,我们还确定了 SCA37 基因型与表型之间的新的显著相关性,并发现了可能导致 DAB1 致病性失调的不同小脑等位基因特异性甲基化特征。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Novel genotype-phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)<sub>n</sub> insertion in spinocerebellar ataxia type 37.

Novel genotype-phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37.

Spinocerebellar ataxia subtype 37 (SCA37) is a rare disease originally identified in ataxia patients from the Iberian Peninsula with a pure cerebellar syndrome. SCA37 patients carry a pathogenic intronic (ATTTC)n repeat insertion flanked by two polymorphic (ATTTT)n repeats in the Disabled-1 (DAB1) gene leading to cerebellar dysregulation. Herein, we determine the precise configuration of the pathogenic 5'(ATTTT)n-(ATTTC)n-3'(ATTTT)n SCA37 alleles by CRISPR-Cas9 and long-read nanopore sequencing, reveal their epigenomic signatures in SCA37 lymphocytes, fibroblasts, and cerebellar samples, and establish new molecular and clinical correlations. The 5'(ATTTT)n-(ATTTC)n-3'(ATTTT)n pathogenic allele configurations revealed repeat instability and differential methylation signatures. Disease age of onset negatively correlated with the (ATTTC)n, and positively correlated with the 3'(ATTTT)n. Geographic origin and gender significantly correlated with age of onset. Furthermore, significant predictive regression models were obtained by machine learning for age of onset and disease evolution by considering gender, the (ATTTC)n, the 3'(ATTTT)n, and seven CpG positions differentially methylated in SCA37 cerebellum. A common 964-kb genomic region spanning the (ATTTC)n insertion was identified in all SCA37 patients analysed from Portugal and Spain, evidencing a common origin of the SCA37 mutation in the Iberian Peninsula originating 859 years ago (95% CI 647-1378). In conclusion, we demonstrate an accurate determination of the size and configuration of the regulatory 5'(ATTTT)n-(ATTTC)n-3'(ATTTT)n repeat tract, avoiding PCR bias amplification using CRISPR/Cas9-enrichment and nanopore long-read sequencing, resulting relevant for accurate genetic diagnosis of SCA37. Moreover, we determine novel significant genotype-phenotype correlations in SCA37 and identify differential cerebellar allele-specific methylation signatures that may underlie DAB1 pathogenic dysregulation.

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来源期刊
Human Genetics
Human Genetics 生物-遗传学
CiteScore
10.80
自引率
3.80%
发文量
94
审稿时长
1 months
期刊介绍: Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.
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