Saffie-Awad Paula, Moller Abraham, Daida Kensuke, Jerez Pilar Alvarez, Chen Zhongbo, Anderson Zachary B, Isayan Mariam, Paquette Kimberly, Gibson Sophia B, Fulcher Madison, Miano-Burkhardt Abigail, Malik Laksh, Baker Breeana, Jarreau Paige, Houlden Henry, Ryten Mina, Gu Bida, Chaisson Mark Jp, Miller Danny E, Chaná-Cuevas Pedro, Blauwendraat Cornelis, Singleton Andrew B, Billingsley Kimberley J
Clínica Santa María, Santiago, Chile.
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 Mar 19:2025.03.17.25323863. doi: 10.1101/2025.03.17.25323863.
Hereditary ataxias are genetically diverse, yet up to 75% remain undiagnosed due to technological and financial barriers. A pathogenic GGC repeat expansion was recently linked to spinocerebellar ataxia type 4 (SCA4), characterized by progressive ataxia and sensory neuropathy, with all reported cases in individuals of Northern European ancestry.
We performed Oxford Nanopore Technologies (ONT) genome long-read sequencing (>115 GB per sample) on a total of 15 individuals from Chile; 14 patients with suspected hereditary movement disorders and one unrelated family member. Variants were identified using PEPPER-Margin-DeepVariant 0.8 (SNVs), Sniffles 2.4 (SVs), and Vamos 2.1.3 (STRs). Ancestry was inferred using GenoTools with reference data from the 1000 Genomes Project, Human Genome Diversity Project, and an Ashkenazi Jewish panel. Haplotype analysis was conducted by phasing SNVs within , and methylation profiling was performed with modbamtools.
We identified GGC repeat expansions (47-55 repeats) in four individuals with progressive ataxia, polyneuropathy, and vermis atrophy. One case presented parkinsonism-ataxia, expanding the phenotype. Longer expansions correlated with earlier onset and greater severity. Hypermethylation was detected on the expanded allele, and haplotype analysis linked ultra-rare variants to distant Swedish ancestry.
This is the first report of SCA4 outside Northern Europe, confirming a shared founder haplotype and expansion instability. The presence of parkinsonism broadens the clinical spectrum. Comprehensive genetic testing across diverse populations is crucial, and long-read sequencing enhances diagnostic yield by detecting repeat expansions and SNVs in a single assay.
遗传性共济失调在基因上具有多样性，但由于技术和经济障碍，高达75%的病例仍未得到诊断。最近，一种致病性GGC重复扩增与4型脊髓小脑共济失调（SCA4）相关，其特征为进行性共济失调和感觉神经病变，所有报告病例均为北欧血统个体。
我们对来自智利的15名个体进行了牛津纳米孔技术（ONT）基因组长读测序（每个样本>115 GB）；14名疑似遗传性运动障碍患者和1名无血缘关系的家庭成员。使用PEPPER-Margin-DeepVariant 0.8（单核苷酸变异）、Sniffles 2.4（结构变异）和Vamos 2.1.3（短串联重复序列）鉴定变异。使用GenoTools并参考来自千人基因组计划、人类基因组多样性计划和一个阿什肯纳兹犹太人群体的参考数据推断血统。通过对单倍型内的单核苷酸变异进行定相进行单倍型分析，并使用modbamtools进行甲基化分析。
我们在4名患有进行性共济失调、多神经病和小脑蚓部萎缩的个体中鉴定出GGC重复扩增（47 - 55个重复）。1例表现为帕金森叠加性共济失调，扩展了该疾病的表型。更长的扩增与更早发病和更严重的病情相关。在扩增的等位基因上检测到高甲基化，单倍型分析将超罕见变异与遥远的瑞典血统联系起来。
这是北欧以外地区关于SCA4的首次报告，证实了共享的奠基者单倍型和扩增不稳定性。帕金森叠加症状的存在拓宽了临床谱。对不同人群进行全面的基因检测至关重要，长读测序通过在一次检测中检测重复扩增和单核苷酸变异提高了诊断率。
