CDC45 – Meier-Gorlin Syndrome

Meier-Gorlin syndrome (MGORS) is a rare autosomal recessive disorder defined by the triad of short stature, microtia and absent or hypoplastic patellae. Biallelic mutations in genes encoding subunits of the pre-replication complex impair origin licensing and underlie MGORS. Recently, CDC45 has been implicated in MGORS and related craniosynostosis spectrum disorders.

In an international cohort of 15 affected individuals from 12 families, biallelic partial loss-of-function CDC45 variants were identified, including splice-site and frameshift alleles, defining a spectrum from syndromic coronal craniosynostosis to classical MGORS ([PMID:27374770]). One recurrent frameshift, c.1180del (p.Thr394Ter), exemplifies the loss-of-function mechanism. Additional reports include a single case with craniosynostosis, anorectal malformation and short stature ([PMID:30986546]) and two affected siblings with MGORS and craniosynostosis carrying a frameshift and a splice-disrupting synonymous variant ([PMID:33639314]).

Inheritance is autosomal recessive, with segregation of biallelic CDC45 variants in familial cases; the sib pair report provided one additional affected relative confirming trans inheritance. Phenotypically, CDC45-related MGORS manifests core features of short stature (HP:0004322) and microtia (HP:0008551) with variable craniosynostosis (HP:0001363) and occasional anorectal anomalies.

Functional studies in patient-derived cells demonstrated reduced full-length CDC45 transcripts and protein levels consistent with partial loss of function ([PMID:27374770]). In vitro splicing assays of the non-canonical exon variant revealed usage of novel acceptor sites yielding premature termination codons ([PMID:33639314]). These data support a haploinsufficiency/partial loss-of-function mechanism that impairs origin firing and cell proliferation.

Collectively, 18 probands across 14 families with concordant segregation and functional data provide strong evidence for the CDC45–Meier-Gorlin syndrome association. CDC45 sequencing should be included in diagnostic panels for MGORS and craniosynostosis, facilitating early molecular diagnosis and management.

References

• American Journal of Human Genetics • 2016 • Mutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis PMID:27374770
• European Journal of Medical Genetics • 2020 • Further delineation of CDC45-related Meier-Gorlin syndrome with craniosynostosis and review of literature. PMID:30986546
• 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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