SEC24D – Cole-Carpenter syndrome type 2

SEC24D (HGNC:10706) is implicated in Cole-Carpenter syndrome type 2 (MONDO:0014573), a rare autosomal recessive skeletal dysplasia. A single reported case of a 24-week fetus presenting with severe perinatal skeletal abnormalities, including foreshortened long bones, multiple fractures, and frontal bossing, was diagnosed with CLCRP2 following exome sequencing that identified compound heterozygous SEC24D variants: maternally inherited c.3031_3040delinsC and c.2676+5del (VUS) (PMID:39780448). The severe phenotype phenocopies perinatally lethal osteogenesis imperfecta and expands the clinical spectrum of SEC24D-related coatopathies. No additional affected relatives have been described, and segregation data are limited to this singleton. This single-proband report currently constitutes the entirety of clinical genetic evidence linking SEC24D to Cole-Carpenter syndrome type 2. Based on one affected proband, the clinical validity classification is Limited.

Functional studies of SEC24D in osteogenesis support a loss-of-function mechanism that is consistent with the CLCRP2 phenotype. In vitro depletion of SEC24D in mesenchymal stem cells and characterization of an osteogenesis imperfecta patient harboring compound heterozygous variants c.2609_2610delGA (p.Arg870ThrfsTer10) and c.938G>A (p.Arg313His) demonstrated impaired osteogenic differentiation, endoplasmic reticulum stress induction, and disruption of the ATF6/TGF-β/Runx2 regulatory loop (PMID:40374976). These experiments confirm that SEC24D is critical for cargo-specific ER export in bone-forming cells, and loss of COPII function underlies the skeletal fragility. While functional data in neuronal cells illustrate broader roles for SEC24D in protein trafficking, no conflicting reports dispute its role in bone development. Additional rare SEC24D variants have been identified as modifiers in orofacial cleft phenotypes, suggesting tissue-specific regulatory effects. Despite the limited number of CLCRP2 cases, the combination of clinical and experimental evidence underscores a plausible gene-disease relationship. SEC24D testing may inform prenatal diagnosis and family planning in suspected Cole-Carpenter syndrome type 2.

References

• American journal of medical genetics. Part A • 2025 • Phenotypic Expansion: Fetus With Cole-Carpenter Type 2 Presenting With Novel Neonatal Lethal Skeletal Dysplasia PMID:39780448
• Communications Biology • 2025 • SEC24D depletion induces osteogenic differentiation deficiency by inactivating the ATF6/TGF-β/Runx2 regulatory loop PMID:40374976

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