Abstract
Spinocerebellar ataxia, autosomal recessive-17 (SCAR17) is a rare hereditary ataxia characterized by ataxic gait, cerebellar signs and occasionally accompanied by intellectual disability and seizures. Pathogenic mutations in the CWF19L1 gene that code for CWF19 like cell cycle control factor 1 cause SCAR17. We report here two unrelated families with the clinical characteristics of global developmental delay, cerebellar ataxia, pyramidal signs, and seizures. Cerebellar atrophy, and T2/FLAIR hypointense transverse pontine stripes were observed in brain imaging. Exome sequencing identified novel homozygous mutations including a splice acceptor site variant c.1375-2 A > G on intron 12 in a male patient and a single nucleotide variant c.452 T > G on exon 5 resulting in a missense variant p.Ile151Ser in the female patient from two unrelated families, respectively. Sanger sequencing confirmed the segregation of these variants in the family members with autosomal recessive inheritance. Transcript analysis of the splice site variant revealed activation of a novel cryptic splice acceptor site on exon 13 resulting in an alternative transcription with a loss of nine nucleotides on exon 13. Translation of this transcript predicted an in-frame deletion of three amino acids p.(459_461del). We also observed a novel exon 13 skipping which results in premature termination of the protein product. Our study expands the phenotype, radiological features, and genotypes known in SCAR17.
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Data availability
The data in this study is available with the corresponding author upon reasonable request. The data are not publicly available due to patient privacy and ethical considerations.
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Acknowledgements
We are grateful to the families for providing informed consent to participate in this study.
Funding
We thank Science and Engineering Research Board (SERB), Department of Science & Technology, Government of India (EMR/2017/004853) for providing funding to carry out a part of this study and for providing research fellowship to Prashant Phulpagar.
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BM and VVH conceived the idea and designed the study. Sample collection, processing, data analysis, and interpretation of the results were performed by BM and PP. Experiments were performed by PP and DT. First draft of the manuscript and Figure illustrations were prepared by PP and VVH. PKP, VVH, RY, and NK performed a clinical assessment of the patient and provided samples. All authors reviewed the manuscript, provided critical comments to improve the draft, and approved the final version of the manuscript.
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This study was approved by the ethics committee at the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore. This study was performed after getting appropriate informed consents from the patient and relatives.
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Phulpagar, P., Holla, V.V., Tomar, D. et al. Novel CWF19L1 mutations in patients with spinocerebellar ataxia, autosomal recessive 17. J Hum Genet 68, 859–866 (2023). https://doi.org/10.1038/s10038-023-01195-5
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DOI: https://doi.org/10.1038/s10038-023-01195-5