CDC45 – Meier-Gorlin syndrome 7

CDC45, encoding a DNA replication pre-initiation complex component, is associated with autosomal recessive Meier-Gorlin syndrome 7. This association is supported by 3 probands (PMID:34000999; PMID:33639314) across 2 unrelated families, presenting with severe fetal growth restriction, craniosynostosis, brachydactyly, microtia and patellar hypoplasia. In a prenatal case, whole-exome sequencing identified compound heterozygous CDC45 mutations including the synonymous c.1416C>T (p.His472=) variant, with antenatal 2D/3D ultrasonography and postmortem 3D-CT confirming growth restriction and craniosynostosis (PMID:34000999). Two affected siblings carried biallelic CDC45 variants, further segregating with craniosynostosis and growth phenotypes (PMID:33639314).

Functional validation via an in vitro splicing assay showed that the synonymous c.1416C>T (p.His472=) change activates cryptic splice acceptor sites in intron 6, leading to transcripts with premature termination codons and likely loss-of-function (PMID:33639314). No animal or cellular models have been described, and the limited number of families constrains definitive classification. Nonetheless, these findings highlight CDC45 as a candidate gene for early prenatal or neonatal diagnosis in cases of growth restriction and craniosynostosis. Key take-home: CDC45 testing should be considered when prenatal ultrasound reveals intrauterine growth retardation and skull malformation suggestive of Meier-Gorlin syndrome 7.

References

• BMC pregnancy and childbirth • 2021 • Prenatal diagnosis of Meier-Gorlin syndrome 7: a case presentation. PMID:34000999
• European journal of medical genetics • 2021 • A synonymous variant in a non-canonical exon of CDC45 disrupts splicing in two affected sibs with Meier-Gorlin syndrome with craniosynostosis. PMID:33639314

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