VPS13B – Cohen Syndrome

Cohen syndrome is a rare autosomal recessive neurodevelopmental disorder caused by biallelic mutations in VPS13B, characterized by postnatal microcephaly, intellectual disability, retinal dystrophy, intermittent neutropenia, truncal obesity, joint hypermobility and characteristic facial features (VPS13B; Cohen Syndrome).

Extensive genetic studies have identified over 150 distinct VPS13B mutations in more than 200 affected individuals, predominantly loss‐of‐function alleles including nonsense, frameshift and splice‐site variants (e.g., c.7095del (p.Ser2366AlafsTer49)) (PMID:32605629). These variants are observed as homozygous in consanguineous pedigrees or compound heterozygous in non‐consanguineous families, with segregation confirmed across multiple unrelated cohorts.

Segregation and founder effects have been demonstrated in diverse populations: a Lebanese family with two affected brothers carrying a homozygous splice‐site VPS13B mutation (PMID:19190672), and a Greek island cohort of 14 patients homozygous for a large intragenic deletion indicating a founder mutation (PMID:18655112).

Functional analyses support haploinsufficiency as the pathogenic mechanism. COH1/VPS13B interacts with RAB6 at the Golgi complex, and patient mutations disrupt Golgi integrity and neuritogenesis in iPSC‐derived neurons, which exhibit reduced neural progenitor proliferation and synaptic deficits (PMID:25492866; PMID:32560273). A Vps13b exon 2–deleted mouse model recapitulates motor and cognitive deficits, reinforcing the gene’s role in neurodevelopment (PMID:31495077).

No substantial conflicting evidence has been reported, although atypical presentations lacking obesity or intellectual disability have been described, expanding the phenotypic spectrum (PMID:24311531).

Overall, the clinical validity of VPS13B‐Cohen syndrome is classified as Definitive by ClinGen, supported by identification in >200 probands across multi‐ethnic cohorts, extensive segregation data, and concordant functional studies. Genetic evidence is Strong, based on widespread biallelic loss‐of‐function variants; functional evidence is Moderate, given consistent cellular and animal model data.

Key Take-home: VPS13B genetic testing is critical for confirming Cohen syndrome in children with intellectual disability, neutropenia or retinal dystrophy, guiding prognosis, management, and genetic counseling.

References

• European Journal of Human Genetics • 2009 • A novel VPS13B mutation in two brothers with Cohen syndrome, cutis verticis gyrata and sensorineural deafness. PMID:19190672
• BMC Medical Genetics • 2020 • A novel VPS13B mutation in Cohen syndrome: a case report and review of literature. PMID:32605629
• The Journal of Biological Chemistry • 2015 • Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. PMID:25492866
• Experimental Neurobiology • 2019 • Spatial Learning and Motor Deficits in Vacuolar Protein Sorting-associated Protein 13b (Vps13b) Mutant Mouse. PMID:31495077
• American Journal of Medical Genetics Part A • 2008 • Cohen syndrome resulting from a novel large intragenic COH1 deletion segregating in an isolated Greek island population. PMID:18655112

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