Journal Article

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

Yu Jin Ng, Alvin, ben Issa, Abir, Fakhfakh, Faiza, Khabou, Boudour, Sahari, Umar Bin Mohamad, Reversade, Bruno, Bouchaala, Wafa, Mbarek, Hamdi, Zeyaul, Islam, Bonnard, Carine, Charfi Triki, Chahnez, Szenker-Ravi, Emmanuelle, Kammoun, Fatma

2024

Overview

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.

• Publisher: Springer Nature Singapore,Nature Publishing Group
• Subject: 45 / 45/100 / 631/208/366 / 631/378/2583 / 692/700/139/1512 / 82 / 82/1 / Adaptor Proteins, Vesicular Transport - genetics / Biomedical and Life Sciences / Biomedicine / Child development / Congenital Disorders of Glycosylation - genetics / Congenital Disorders of Glycosylation - pathology / Diagnosis / Electromyography / Exome Sequencing / Female / Gene Expression / Gene frequency / Gene Function / Gene Therapy / Genetics / Genomes / Genomics / Genotype & phenotype / Human Genetics / Humans / Magnetic resonance imaging / Male / Medicine / Molecular Medicine / Molecular modelling / Mutation, Missense / Next-generation sequencing / Patients / Pedigree / Polymorphism, Single Nucleotide / Proteins / Solubility / Tunisia / Whole genome sequencing