SEC24D – Cole-Carpenter syndrome

Autosomal recessive SEC24D variants have been identified in two unrelated patients with clinically confirmed Cole-Carpenter syndrome (CCS). The first reported case was a 7-year-old boy carrying compound heterozygous truncating c.613C>T (p.Gln205Ter) and missense c.3044C>T (p.Ser1015Phe) alleles within a 14 Mb founder haplotype (PMID:25683121). A second Japanese adolescent exhibited biallelic c.938G>A (p.Arg313His) and c.1450C>T (p.Arg484Ter) variants (PMID:30462379). No additional affected relatives were documented, consistent with autosomal recessive inheritance. Functional studies demonstrated that patient fibroblasts display impaired COPII-mediated procollagen export and dilated ER tubules, recapitulating Sec24d-deficient zebrafish phenotypes (PMID:25683121; PMID:19020038). Affected individuals share features including short stature (HP:0004322), basilar impression (HP:0005758), ocular proptosis, frontal bossing, midface hypoplasia, and micrognathia. In aggregate, these data support that biallelic SEC24D loss-of-function underlies AR CCS by disrupting COPII cargo selection — reinforcing its utility in genetic diagnosis and potential COPII-targeted therapies.

References

• American journal of human genetics • 2015 • Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta. PMID:25683121
• American journal of medical genetics. Part A • 2018 • Japanese patient with Cole-carpenter syndrome with compound heterozygous variants of SEC24D. PMID:30462379
• The Journal of neuroscience • 2008 • Sec24- and ARFGAP1-dependent trafficking of GABA transporter-1 is a prerequisite for correct axonal targeting. PMID:19020038

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