To characterize the genetic background of molecularly undefined childhood-onset ataxias in Finland.

This study examined a cohort of patients from 50 families with onset of an ataxia syndrome before the age of 5 years collected from a single tertiary center, drawing on the advantages offered by next generation sequencing. A genome-wide genotyping array (Illumina Infinium Global Screening Array MD-24 v.2.0) was used to search for copy number variation undetectable by exome sequencing.

Exome sequencing led to a molecular diagnosis for 20 probands (40%). In the 23 patients examined with a genome-wide genotyping array, 2 additional diagnoses were made. A considerable proportion of probands with a molecular diagnosis had de novo pathogenic variants (45%). In addition, the study identified a de novo variant in a gene not previously linked to ataxia: MED23. Patients in the cohort had medically actionable findings.

There is a high heterogeneity of causative mutations in this cohort despite the defined age at onset, phenotypical overlap between patients, the founder effect, and genetic isolation in the Finnish population. The findings reflect the heterogeneous genetic background of ataxia seen worldwide and the substantial contribution of de novo variants underlying childhood ataxia.

描述芬兰分子未定义的儿童期发作性共济失调的遗传背景。

这项研究利用下一代测序提供的优势，从一个三级中心收集了来自 50 个家庭的 5 岁前出现共济失调综合征的患者队列。全基因组基因分型阵列（Illumina Infinium Global Screening Array MD-24 v.2.0）用于搜索外显子组测序无法检测到的拷贝数变异。

外显子组测序对 20 名先证者（40%）进行了分子诊断。在使用全基因组基因分型阵列检查的 23 名患者中，做出了另外 2 名诊断。具有分子诊断的相当大比例的先证者具有从头致病变异（45％）。此外，该研究在以前与共济失调无关的基因中发现了一个从头变异：MED23。队列中的患者有医学上可行的发现。

尽管在芬兰人群中定义了发病年龄、患者之间的表型重叠、创始人效应和遗传隔离，但该队列中的致病突变存在高度异质性。这些发现反映了世界范围内共济失调的异质遗传背景以及儿童共济失调的从头变异的重大贡献。