COPB2 – Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome

Evidence supporting an association between COPB2 (HGNC:2232) and blepharophimosis, ptosis, and epicanthus inversus syndrome (MONDO_0007201) is presently limited. A single de novo 197‑kb deletion event that encompasses COPB2, along with MRPS22 and regulatory elements for FOXL2, was reported in a prepubertal girl exhibiting classical BPES features—namely blepharophimosis, ptosis, and epicanthus inversus—as well as additional findings including cleft soft palate and microcephaly (PMID:31191203). While the deletion was identified in this isolated case, no further independent pathogenic variants in COPB2 have been reported in BPES, and segregation data beyond the proband are lacking.

The genetic evidence is therefore constrained to this singular CNV event with no corroborative case series for COPB2 in BPES. Although functional studies in COPB2 have been conducted, these were performed in the context of isolated congenital microcephaly, employing variants such as c.760C>T (p.Arg254Cys) to model defective embryogenesis and corticogenesis (PMID:29036432; PMID:37734708). Such assays do not recapitulate the BPES phenotype, and no direct functional data currently links COPB2 disruption specifically to blepharophimosis, ptosis, and epicanthus inversus syndrome.

In summary, while the observed deletion offers a hint toward a contributory role of COPB2 in BPES, the evidence is complicated by its occurrence within a larger genomic interval that also affects recognized BPES determinants. The clinical validity remains limited, necessitating further investigation to clarify whether COPB2 independently contributes to BPES pathogenesis.

Key Take‑home: Despite intriguing genomic findings, the current evidence for COPB2’s association with BPES is limited and should be interpreted with caution in diagnostic contexts.

References

• Molecular Syndromology • 2019 • Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome: New Report with a 197-kb Deletion Upstream of FOXL2 and Review of the Literature PMID:31191203
• Human Molecular Genetics • 2017 • Copb2 is essential for embryogenesis and hypomorphic mutations cause human microcephaly PMID:29036432
• European Journal of Medical Genetics • 2023 • Novel insight into the phenotype of microcephaly 19 in the patient with missense COPB2 mutation PMID:37734708

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