Cuillerier Alexanne, Del Gobbo Giulia F, Mackay Layla, Wall Erika, Couse Madeline, McDonell Laura M, Cloutier Mireille, Danzi Matt C, Warman-Chardon Jodi, Bourque Pierre R, Suchowersky Oksana, Mears Alan, Seldenthuis Luke, Mears Wendy, Larrigan Laura, White-Brown Alexandre, Pfeffer Gerald, Bulman Dennis E, Dyment David, Boycott Kym M
Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
University of Ottawa, Ottawa, Ontario, Canada.
Ann Clin Transl Neurol. 2025 Apr 7. doi: 10.1002/acn3.70016.
Spinocerebellar ataxias (SCA) represent a clinically and genetically heterogeneous group of progressive neurodegenerative diseases with prominent cerebellar atrophy. Recently, a novel pathogenic repeat expansion in intron 1 of FGF14 was identified, causing adult-onset SCA (SCA27B). We aimed to determine the proportion of our unsolved adult-onset ataxia cohort harboring this expansion using several technologies, and to characterize the phenotypic presentation within our population.
Individuals presenting with adult-onset ataxia (> 30 years old) and negative previous genetic testing were selected from the Care4Rare patient repository. Affected individuals were from all ethnicities, and 90% had a family history suggestive of dominant ataxia, representing 19 of the 23 families included. We used multiple tools (PCR, long-read genome sequencing and optical genome mapping (OGM)) to identify the pathogenic GAA repeat in FGF14.
Of the 23 families included in this study, 65.2% harbored a pathogenic GAA expansion in FGF14. Individuals of French-Canadian descent (FC) represented most of our cohort and had a 64.7% diagnostic yield. Affected individuals presented with gaze-evoked nystagmus, gait ataxia, cerebellar dysarthria, and early episodic features. The GAA expansion in FGF14 was visible by OGM in all individuals tested.
Our diagnostic yield demonstrates this expansion may be the most common cause of adult-onset SCA in dominant families of FC ancestry. Our FC participants have a phenotype distinct from previously published FC patients, with gaze-evoked nystagmus being the most common eye anomaly. From a diagnostic standpoint, the pathogenic GAA repeat can be identified by OGM, but additional tests are required to complement the interpretation.
脊髓小脑共济失调（SCA）是一组临床和遗传异质性的进行性神经退行性疾病，伴有明显的小脑萎缩。最近，在FGF14基因内含子1中发现了一种新的致病性重复扩增，导致成人发病的SCA（SCA27B）。我们旨在使用多种技术确定未解决的成人发病共济失调队列中携带这种扩增的比例，并描述我们人群中的表型表现。
从Care4Rare患者资料库中选取成人发病共济失调（>30岁）且既往基因检测阴性的个体。受影响个体来自所有种族，90%有提示显性共济失调的家族史，包括23个家族中的19个。我们使用多种工具（PCR、长读长基因组测序和光学基因组图谱（OGM））来鉴定FGF14基因中的致病性GAA重复序列。
在本研究纳入的23个家族中，65.2%在FGF14基因中存在致病性GAA扩增。法裔加拿大血统（FC）个体占我们队列的大多数，诊断率为64.7%。受影响个体表现为凝视诱发性眼球震颤、步态共济失调、小脑性构音障碍和早期发作性特征。在所有检测个体中，OGM均可检测到FGF14基因中的GAA扩增。
我们的诊断率表明，这种扩增可能是FC血统显性家族中成人发病SCA的最常见原因。我们的FC参与者具有与先前发表的FC患者不同的表型，凝视诱发性眼球震颤是最常见的眼部异常。从诊断角度来看，OGM可以识别致病性GAA重复序列，但需要额外的检测来辅助解读。
