Abstract
The clinical diagnosis of patients with multisystem involvement including a pronounced neurologic damage is challenging. High-throughput sequencing methods remains crucial to provide an accurate diagnosis. In this study, we reported a Tunisian patient manifesting hypotonia and global developmental delay with visual and skin abnormalities. Exome sequencing was conducted followed by segregation analysis and, subsequently additional investigations. In silico analysis of non-synonymous variants (nsSNPs) described in COG5 in conserved positions was made. Results revealed a homozygous missense variant c.298 C > T (p.Leu100Phe) in the COG5 inherited from both parents. This variant altered both protein solubility and stability, in addition to a putative disruption of the COG5-COG7 interaction. This disruption has been confirmed using patient-derived cells in vitro in a COG5 co-immuno-precipitation, where interaction with binding partner COG7 was abrogated. Hence, we established the COG5-CDG diagnosis. Clinically, the patient shared common features with the already described cases with the report of the ichtyosis as a new manifestation. Conversely, the CADD scoring revealed 19 putatively pathogenic nsSNPs (Minor Allele Frequency MAF < 0.001, CADD > 30), 11 of which had a significant impact on the solubility and/or stability of COG5. These properties seem to be disrupted by six of the seven missense COG5-CDG variants. In conclusion, our study expands the genetic and phenotypic spectrum of COG5-CDG disease and highlight the utility of the next generation sequencing as a powerful tool in accurate diagnosis. Our results shed light on a likely molecular mechanism underlying the pathogenic effect of missense COG5 variants, which is the alteration of COG5 stability and solubility.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Acknowledgements
We would like to thank the studied family for the cooperation to perform the present study. We are also grateful to the entire team of Child neurology departement in the CHU Hedi Chaker of Sfax for their help and availability.
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BK: conceptualization, methodology, formal analysis, interpretation of data, writing original draft, review & editing; US: elaborating the functional analysis, review& editing; ABI, WB : Contributed to the collection and the analysis of clinical data, ES-R, AYJN, CB : contributed with reagents/materials necessary for the functional analysis, reviewed the final draft of the manuscript, HM : design of work, interpretation of data, reviewed the final draft of the manuscript, IZ : Performed and analyzed the Modeling study, FF: contributed with reagents/materials necessary for the segregation analysis, reviewed the final draft of the manuscript, FK: contributed with the analysis of the clinical data, BR : performing and interpretation of the WES data, supervising the functional study, reviewed the final draft of the manuscript, CCT : conceived and designed the study, supervise data analysis and reviewed drafts of the paper. All authors have approved the manuscript and agree with the submission.
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The study was conducted according to the guidelines ofthe Declaration of Helsink and approved by the Regional ethics Committee of the Protection of Persons, Sfax, Tunisia (CPP SUD) (number 0193/2019).
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Khabou, B., Sahari, U.B.M., ben Issa, A. et al. Characterization of a missense variant in COG5 in a Tunisian patient with COG5-CDG syndrome and insights into the effect of non-synonymous variants on COG5 protein. J Hum Genet 69, 591–597 (2024). https://doi.org/10.1038/s10038-024-01273-2
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DOI: https://doi.org/10.1038/s10038-024-01273-2
