Abstract
Joubert syndrome (JBTS) is characterized by a magnetic resonance imaging appearance called ‘molar tooth sign’, neonatal breathing dysregulation and hypotonia, and developmental delay. Whole-exome analysis based on short-read sequencing has often contributed to the identification of causative single-nucleotide variants in patients clinically diagnosed with JBTS. However, ~10% of them are still undiagnosed even though a single possible pathogenic variant has been identified. We report a successful identification of biallelic variants using long-read whole-genome sequencing and haplotype phasing analysis in a family with two Japanese siblings having morphological brain abnormalities. The affected siblings had a novel nonsynonymous variant (CC2D2A:NM_001080522.2:c.4454A>G:p.(Tyr1485Cys)) and an exonic insertion of Long INterspercsed Element-1 (LINE-1). The allelicity of these variants was clearly proven without the data of parents. Finally, our survey of in-house genome sequencing data indicates that there are rare carriers of CC2D2A related diseases, who harbour the exonic LINE-1 insertion in the CC2D2A gene.
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Data availability
The raw datasets are available from the corresponding authors upon reasonable request.
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Acknowledgements
The authors would like to express our sincere thanks to the families, clinicians, and medical staff who took part in this presentation. We would like to thank Meiko Takeshita and Makiko Omata for sequencing analysis, and Yukimi Abe for management of samples and information. We also would like to thank Hemant Thapar for providing computing equipment.
Funding
Our work described herein was aided by grants funding JSPS KAKENHI Scientific Research (C), 20K09916 (KY) and Japan Agency for Medical Research and Development, 22ek0109549s0202 (YM).
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The patients and their mothers gave written informed consent for genetic testing and the study was approved by the National Research Institute for Child Health and Development, and Initiative on Rare and Undiagnosed Disease in Pediatrics (IRUD-P), Japan (https://www.amed.go.jp/en/index.html).
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Yanagi, K., Coker, J., Miyana, K. et al. Biallelic CC2D2A variants, SNV and LINE-1 insertion simultaneously identified in siblings using long-read whole-genome sequencing and haplotype phasing. J Hum Genet 68, 431–435 (2023). https://doi.org/10.1038/s10038-023-01130-8
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DOI: https://doi.org/10.1038/s10038-023-01130-8
