CDC6 – Meier-Gorlin Syndrome

Meier-Gorlin syndrome (MGS) is an autosomal recessive primordial dwarfism characterized by microtia, patellar hypoplasia, and short stature. CDC6 encodes a key replication licensing factor in the pre-replication complex. In 2011, a homozygous NM_001254.4:c.968C>G (p.Thr323Arg) variant was identified in an individual presenting with the MGS triad (PMID:21358632). In 2022, compound heterozygous NM_001254.3:c.230A>G (p.Lys77Arg) and NM_001254.3:c.232C>T (p.Gln78Ter) were reported in a female with MGS5 features including progeroid appearance and lipodystrophy (PMID:35023948). To date, 3 unrelated probands with biallelic CDC6 variants—two missense and one protein-truncating—have been described under an autosomal recessive inheritance model; no extended segregation data are available.

Functional studies in Saccharomyces cerevisiae demonstrate that amino acid substitutions at the conserved ATP-binding Lys114 site abrogate DNA synthesis and Mcm5 loading, indicating loss-of-function (PMID:10075735; PMID:10945234). A zebrafish hypomorphic cdc6tsu21cd mutant modeling the human p.Thr323Arg change exhibits embryonic survival, post-natal growth retardation, microcephaly and reproductive defects analogous to MGS (PMID:28985365). Taken together, the evidence meets a Limited clinical validity classification per ClinGen criteria due to the small number of probands and absence of segregation, though functional concordance is supportive. CDC6 should be included in genetic testing panels for patients with MGS features to improve diagnosis and counseling.

References

• Nature Genetics • 2011 • Mutations in the pre-replication complex cause Meier-Gorlin syndrome PMID:21358632
• The Application of Clinical Genetics • 2022 • Novel Compound Heterozygous Variants in the CDC6 Gene in a Russian Patient with Meier-Gorlin Syndrome PMID:35023948
• The Journal of Biological Chemistry • 1999 • The essential role of Saccharomyces cerevisiae CDC6 nucleotide-binding site in cell growth, DNA synthesis, and Orc1 association PMID:10075735
• DNA and Cell Biology • 2000 • Loss control of Mcm5 interaction with chromatin in cdc6-1 mutated in CDC-NTP motif PMID:10945234
• Human Molecular Genetics • 2017 • Zebrafish cdc6 hypomorphic mutation causes Meier-Gorlin syndrome-like phenotype PMID:28985365

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