Akçimen Fulya, Daida Kensuke, Lange Lara M, Moller Abraham, Miano-Burkhardt Abigail, Malik Laksh, Paquette Kimberly, Jerez Pilar Alvarez, Mingle Jackson, Baker Breeana, Meredith Melissa, Kouam Cedric, Jarreau Paige, Markham Androo, Anderson Jessica, Jain Miten, Chaisson Mark, Cookson Mark, Casey Bradford, Iwaki Hirotaka, Bandres-Ciga Sara, Saffie-Awad Paula, Nalls Mike, Fang Zih-Hua, Singleton Andrew B, Blauwendraat Cornelis, Billingsley Kimberley J
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
medRxiv. 2025 Aug 19:2025.08.14.25333596. doi: 10.1101/2025.08.14.25333596.
Pathogenic GAA repeat expansions in are an established cause of late-onset cerebellar ataxia, but have not been linked to Parkinson's disease (PD). Given emerging evidence that repeat expansions in ataxia-associated genes like , can contribute to atypical or familial forms of PD, we investigated whether expansions might play a similar role. Using long-read whole-genome sequencing on 411 individuals with PD and 197 neurologically healthy controls from the PPMI cohort, alongside 1,429 additional controls from the NIH CARD initiative, the 1000 Genomes Project, and the All of Us program, representing globally diverse populations. We identified pathogenic GAA repeat expansions in five individuals with PD and one control. All five individuals fit the clinical criteria of PD and showed typical patterns of neurodegeneration on DaTSCAN imaging; α-synuclein aggregation was confirmed by a positive seeding assay among four individuals with available data. These findings broaden the phenotypic spectrum of repeat-associated disease and suggest a rare, previously unrecognized genetic contributor to PD. To our knowledge, this is the first report implicating in PD and underscores the utility of long-read sequencing for detecting hidden forms of pathogenic variation in unresolved cases.
致病的GAA重复扩增是迟发性小脑共济失调的既定病因，但尚未与帕金森病（PD）相关联。鉴于新出现的证据表明，像[具体基因]这样的共济失调相关基因中的重复扩增可能导致非典型或家族性形式的PD，我们研究了[具体基因]扩增是否可能发挥类似作用。我们对PPMI队列中的411名PD患者和197名神经健康对照进行了长读长全基因组测序，同时还对来自美国国立卫生研究院CARD计划、千人基因组计划和“我们所有人”计划的另外1429名对照进行了测序，这些对照代表了全球不同人群。我们在5名PD患者和1名对照中鉴定出致病的[具体基因]GAA重复扩增。所有5名患者均符合PD的临床标准，并且在DaTSCAN成像上显示出典型的神经退行性变模式；在有可用数据的4名患者中，通过阳性种子试验证实了α-突触核蛋白聚集。这些发现拓宽了[具体基因]重复相关疾病的表型谱，并提示了一种罕见的、以前未被认识的PD遗传因素。据我们所知，这是首次报道[具体基因]与PD有关，并强调了长读长测序在检测未解决病例中隐藏形式的致病变异方面的实用性。
