Purpose

Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families.

Methods

We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines.

Results

We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation.

Conclusion

A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.

中文翻译：

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作为遗传性共济失调和相关疾病原因的高亚型变异率：对 366 个家庭的队列研究

目的

鉴于各种原因的巨大异质性和临床重叠，遗传性共济失调和相关疾病的诊断是一项真正的挑战。我们通过对一大群未确诊的家庭进行测序来评估这些疾病的分子诊断效果。

方法

我们通过临床外显子组捕获测序分析了 366 名未确诊的共济失调或相关疾病的连续患者。计算机分析是使用内部管道进行的，该管道结合了变体排名和拷贝数变体 (CNV) 搜索。根据美国医学遗传学和基因组学/分子病理学协会 (ACMG/AMP) 指南解释变体。

结果

我们在 46% 的病例中建立了分子诊断。我们确定了 35 名轻度受影响的患者，其基因中的致病变异通常与严重的表现相关。这些病例的解释是发生了亚型变异，但也很少怀疑机制，如 C 末端截断和翻译重新启动。

结论

临床异质性和表型重叠的很大一部分是由难以识别且不易预测的亚形态变异解释的。我们发现的亚态 C 末端截断和翻译重新启动机制可能仅适用于少数基因，因为它依赖于特定的域组织和改变。我们将PEX10和FASTKD2确定为翻译重新启动的候选者，以解释轻度疾病的表现。