Autosomal Recessive Spinocerebellar Ataxia 20, SCAR20, is a rare condition characterized by intellectual disability, lack of speech, ataxia, coarse facies and macrocephaly, caused by SNX14 variants. While all cases described are due to homozygous variants that generally result in loss of protein, so far there are no other cases of reported compound heterozygous variants. Here we describe the first non-consanguineous SCAR20 family, the second Portuguese, with two siblings presenting similar clinical features caused by compound heterozygous SNX14 variants: NM_001350532.1:c.1195C>T, p.(Arg399^*) combined with a novel complex genomic rearrangement. Quantitative PCR (Q-PCR), long-range PCR and sequencing was used to elucidate the region and mechanisms involved in the latter: two deletions, an inversion and an AG insertion: NM_001350532.1:c.[612+3028_698-2759del;698-2758_698-516inv;698-515_1171+1366delinsAG]. In silico analyses of these variants are in agreement with causality, enabling a genotype-phenotype correlation in both patients. Clinical phenotype includes dystonia and stereotypies never associated with SCAR20. Overall, this study allowed to extend the knowledge of the phenotypic and mutational spectrum of SCAR20, and to validate the role of Sorting nexin-14 in a well-defined neurodevelopmental syndrome, which can lead to cognitive impairment. We also highlight the value of an accurate clinical evaluation and deep phenotyping to disclose the molecular defect underlying highly heterogeneous condition such as intellectual disability.

常染色体隐性脊髓小脑共济失调症20（SCAR20）是一种罕见疾病，其特征是智力障碍，言语不足，共济失调，粗面相和大头畸形，原因是 SNX14变体。尽管所描述的所有情况都是由于通常导致蛋白质损失的纯合变异体引起的，但迄今为止，尚无其他报道的化合物杂合变异体案例。在这里，我们描述了第一个非血缘SCAR20家族，第二个葡萄牙语，两个兄弟姐妹表现出由复合杂合子引起的相似临床特征SNX14变体：NM_001350532.1：c.1195C> T，p。（Arg399 ^*）与新颖的复杂基因组重排组合。使用定量PCR（Q-PCR），远程PCR和测序来阐明后者所涉及的区域和机制：两个缺失，一个倒置和一个AG插入：NM_001350532.1：c。[612 + 3028_698-2759del; 698-2758_698-516inv; 698-515_1171 + 1366delinsAG]。电脑这些变异的分析与因果关系一致，从而使两名患者的基因型与表型相关。临床表型包括从未与SCAR20相关的肌张力障碍和刻板印象。总体而言，这项研究可以扩展SCAR20的表型和突变谱的知识，并可以验证Sorting nexin-14在明确定义的神经发育综合征中的作用，这可能导致认知障碍。我们还强调了准确的临床评估和深入的表型分析的价值，以揭示高度异质性疾病（例如智力残疾）背后的分子缺陷。