C9orf72 Repeat Expansion Discordance in 6 Multigenerational Kindreds.

IF 3 3区 医学 Q2 CLINICAL NEUROLOGY
Neurology-Genetics Pub Date : 2023-12-22 eCollection Date: 2024-02-01 DOI:10.1212/NXG.0000000000200112
Marie Ryan, Mark A Doherty, Ahmad Al Khleifat, Emmet Costello, Jennifer C Hengeveld, Mark Heverin, Ammar Al-Chalabi, Russell L Mclaughlin, Orla Hardiman
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引用次数: 0

Abstract

Background and objectives: A hexanucleotide repeat expansion in the noncoding region of the C9orf72 gene is the most common genetically identifiable cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in populations of European ancestry. Pedigrees associated with this expansion exhibit phenotypic heterogeneity and incomplete disease penetrance, the basis of which is poorly understood. Relatives of those carrying the C9orf72 repeat expansion exhibit a characteristic cognitive endophenotype independent of carrier status. To examine whether additional shared genetic or environmental risks within kindreds could compel this observation, we have conducted a detailed cross-sectional study of the inheritance within multigenerational Irish kindreds carrying the C9orf72 repeat expansion.

Methods: One hundred thirty-one familial ALS pedigrees, 59 of which carried the C9orf72 repeat expansion (45.0% [95% CI 36.7-53.5]), were identified through the Irish population-based ALS register. C9orf72 genotyping was performed using repeat-primed PCR with amplicon fragment length analysis. Pedigrees were further investigated using SNP, targeted sequencing data, whole-exome sequencing, and whole-genome sequencing.

Results: We identified 21 kindreds where at least 1 family member with ALS carried the C9orf72 repeat expansion and from whom DNA was available from multiple affected family members. Of these, 6 kindreds (28.6% [95% CI 11.8-48.3]) exhibited discordant segregation. The C9orf72 haplotype was studied in 2 families and was found to segregate with the C9orf72-positive affected relative but not the C9orf72-negative affected relative. No other ALS pathogenic variants were identified within these discordant kindreds.

Discussion: Family members of kindreds associated with the C9orf72 repeat expansion may carry an increased risk of developing ALS independent of their observed carrier status. This has implications for assessment and counseling of asymptomatic individuals regarding their genetic risk.

6 个多代亲属中的 C9orf72 重复扩展不一致。
背景和目的:在欧洲血统的人群中,C9orf72 基因非编码区的六核苷酸重复扩增是肌萎缩性脊髓侧索硬化症(ALS)和额颞叶痴呆症最常见的遗传学可识别病因。与这一扩增相关的父系表现出表型异质性和不完全的疾病穿透性,其原因尚不清楚。C9orf72重复扩增携带者的亲属表现出与携带者身份无关的特征性认知内表型。为了研究是否有其他共同的遗传或环境风险可能导致这一结果,我们对携带 C9orf72 重复扩增的爱尔兰多代亲属的遗传情况进行了详细的横断面研究:通过爱尔兰 ALS 人口登记册确定了 131 个家族 ALS 血统,其中 59 个携带 C9orf72 重复扩增(45.0% [95% CI 36.7-53.5])。C9orf72 基因分型是通过重复引物 PCR 和扩增片段长度分析进行的。利用 SNP、靶向测序数据、全外显子组测序和全基因组测序对血统进行了进一步调查:结果:我们确定了 21 个至少有一名 ALS 患者携带 C9orf72 重复扩增的家族成员,并且可以从多个受影响的家族成员中获得 DNA。其中,6 个家族(28.6% [95% CI 11.8-48.3])表现出不和谐的分离。对 2 个家族中的 C9orf72 单倍型进行了研究,结果发现,C9orf72 阳性的患病亲属与 C9orf72 阴性的患病亲属发生了分离。在这些不一致的家族中没有发现其他 ALS 致病变体:讨论:与 C9orf72 重复扩增相关的家族成员罹患 ALS 的风险可能会增加,这与其观察到的携带者身份无关。这对评估无症状个体的遗传风险并为其提供咨询具有重要意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neurology-Genetics
Neurology-Genetics Medicine-Neurology (clinical)
CiteScore
6.30
自引率
3.20%
发文量
107
审稿时长
15 weeks
期刊介绍: Neurology: Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. Original articles in all areas of neurogenetics will be published including rare and common genetic variation, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease-genes, and genetic variations with a putative link to diseases. This will include studies reporting on genetic disease risk and pharmacogenomics. In addition, Neurology: Genetics will publish results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology: Genetics, but studies using model systems for treatment trials are welcome, including well-powered studies reporting negative results.
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