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Identification of a deep intronic POLR3A variant causing inclusion of a pseudoexon derived from an Alu element in Pol III-related leukodystrophy

Journal of Human Genetics volume 65, pages 921–925 (2020)Cite this article

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Abstract

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.

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Acknowledgements

We would like to thank the patient’s family for participating in this work. This work was supported by Grant‐in‐Aid from the Ministry of Health, Labour and Welfare of Japan; the Takeda Science Foundation, and a HUSM Grant-in-Aid from Hamamatsu University School of Medicine.

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  1. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Takuya Hiraide, Mitsuko Nakashima & Hirotomo Saitsu

  2. Department of Pediatrics, Jichi Medical School, Shimotsuke, Japan

    Takahiro Ikeda, Daisuke Tanaka & Hitoshi Osaka

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  1. Takuya Hiraide
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Correspondence to Hirotomo Saitsu.

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Hiraide, T., Nakashima, M., Ikeda, T. et al. Identification of a deep intronic POLR3A variant causing inclusion of a pseudoexon derived from an Alu element in Pol III-related leukodystrophy. J Hum Genet 65, 921–925 (2020). https://doi.org/10.1038/s10038-020-0786-y

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