Abstract
Cohen syndrome (CS) is an autosomal recessive congenital disorder characterized by mutation in the vacuolar protein sorting 13 homolog B (VPS13B; formerly COH1) gene. In the current study, a Chinese family has two young sibling cases having a developmental delay, physical obesity, high myopia, and a special face, which suspected to be CS. The purpose of the study was to identify variants and further analyze their pathogenicity for CS. Next-generation sequencing (NGS) revealed a compound heterozygous mutation in VPS13B gene in the proband, which comprises a frameshift mutation in NM_017890.4: c.10076_10077delCA (p.T3359fs*29) and a putative splice site mutation in c.6940 + 1G > T. Both Minigene assay in vitro and splicing assay in vivo confirmed that the splicing mutation in c.6940 + 1G > T generates a frameshift transcript with whole exon 38 skipping. Eventually, quantitative real-time PCR demonstrated that either of the two mutations can lead to degradation of the VPS13B gene at the transcriptional level. Functional studies of variants identified in CS patients are essential for their subsequent genetic counseling and prenatal diagnoses and could also be the start point for new therapeutic approaches, currently based only on symptomatic treatment.
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Abbreviations
- VPS13B:
-
vacuolar protein sorting 13, yeast, homolog of B
- CS:
-
Cohen syndrome
- NGS:
-
Next-generation sequencing
- CMA:
-
chromosomal microarray analysis
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Acknowledgments
We thank the studied family for their understanding and cooperation.
Funding
National Natural Science Foundation of China , Grant/Award Numbers: 31401103; National Natural Science Foundation of Henan Province, Grant/Award Numbers:172102310296; The Technology Innovation Committee of Grant/Award Numbers:172102310296.
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Yuanyin Zhao designed the analyzed data and co-wrote the paper. Guiyu Lou performed experiments, analyzed data, and co-wrote the paper. Yang Ke and Yuwei Zhang performed experiments. Samaa Abdelmonem Shama: Writing modification;
Na Qi and Litao Qin: bioinformatic analyses. Liangjie Guo: clinic data collection.
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Highlight
A compound heterozygous mutation in VPS13B gene was identified in a Chinese Cohen syndrome family.
This splice site variant generates a frameshift transcript with whole exon skipping.
Either of the two mutations can lead to degradation of the VPS13B gene at the transcriptional level in vivo.
Splice site variant in NM_017890.4: c.6940 + 1G > T detected in three sporadically Chinese CS families could be a recurrent mutation for CS in Chinese population.
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Lou, G., Ke, Y., Zhang, Y. et al. Functional Analysis of a Compound Heterozygous Mutation in the VPS13B Gene in a Chinese Pedigree with Cohen Syndrome. J Mol Neurosci 71, 943–952 (2021). https://doi.org/10.1007/s12031-020-01713-6
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DOI: https://doi.org/10.1007/s12031-020-01713-6