Pseudoexon inclusion caused by deep intronic variants is an important genetic cause for various disorders. Here, we present a case of a hypomyelinating leukodystrophy with developmental delay, intellectual disability, autism spectrum disorder, and hypodontia, which are consistent with autosomal recessive POLR3-related leukodystrophy. Whole-exome sequencing identified only a heterozygous missense variant (c.1451G>A) in POLR3A. To explore possible involvement of a deep intronic variant in another allele, we performed whole-genome sequencing of the patient with variant annotation by SpliceAI, a deep-learning-based splicing prediction tool. A deep intronic variant (c.645 + 312C>T) in POLR3A, which was predicted to cause inclusion of a pseudoexon derived from an Alu element, was identified and confirmed by mRNA analysis. These results clearly showed that whole-genome sequencing, in combination with deep-learning-based annotation tools such as SpliceAI, will bring us further benefits in detecting and evaluating possible pathogenic variants in deep intronic regions.

深度内含子变异导致的假性外显子包涵体是导致各种疾病的重要遗传原因。在这里，我们提出了一个发育迟缓，智力障碍，自闭症谱系障碍和牙髓不足的低髓鞘性白细胞营养不良的病例，这与常染色体隐性POLR3相关性白细胞营养不良是一致的。全外显子组测序仅在POLR3A中鉴定出杂合的错义变体（c.1451G> A）。为了探索深度内含子变异体可能在另一个等位基因中的参与，我们通过基于深度学习的剪接预测工具SpliceAI对患者进行了全基因组测序，并带有变异体注释。深内含子变体（c.645 + 312C> T）在POLR3A，其被预测为原因包含衍生自一个pseudoexon的铝通过mRNA分析鉴定并确认了该元素。这些结果清楚地表明，全基因组测序与基于深度学习的注释工具（例如SpliceAI）相结合，将为我们带来更多的好处，可用于检测和评估深内含子区域的可能病原体变异。