Cohen Syndrome is predominantly caused by rare homozygous or compound heterozygous pathogenic variants in the VPS13B gene, which disrupt protein translation and lead to a loss of function. The widespread use of next-generation sequencing in genetic diagnostics has increased the detection of variants of unknown clinical significance (VUS) in the VPS13B gene, necessitating further functional validation to determine their pathogenicity.
A recent study presented a family with two Cohen Syndrome patients who carried four rare VPS13B variants. These variants challenged the interpretation of their disease-causing role. To overcome this limitation, researchers established a cellular detection assay that measures the subcellular distribution of the encoded VPS13B protein in the Golgi apparatus and the cytosol.
The functional characterization of one of the missense variants (c.710G > C, p.Arg237Pro) showed diminished localization at the Golgi complex, highlighting its clinical relevance. This finding supported its classification by the American College of Medical Genetics and Genomics (ACMG) as likely pathogenic. The study demonstrates that functional evidence provides much stronger validation for the pathogenic character of a genetic variant than in silico predictions alone.
The researchers emphasize the importance of combining genetic and functional testing of VPS13B missense variants to ensure accurate molecular diagnosis and personalized medical care for Cohen Syndrome patients. This approach can help resolve the uncertainty surrounding VUS and improve the genetic counseling provided to affected families.
Medical Disclaimer: This information is for educational purposes only and does not constitute medical advice. Genetic testing and clinical management should be performed by qualified healthcare professionals.