CDC6 – Meier-Gorlin Syndrome 5

CDC6 encodes a component of the pre-replication complex essential for origin licensing, and biallelic CDC6 mutations cause Meier-Gorlin syndrome 5 (MGS5), an autosomal recessive primordial dwarfism with microtia, patellar hypoplasia, and growth retardation. Only one male patient with a homozygous CDC6 missense variant has been reported to date. A second unrelated female patient from Russia was found to carry compound heterozygous CDC6 variants, c.230A>G (p.Lys77Arg) and c.232C>T (p.Gln78Ter), and presented with severe postnatal growth failure, progeroid appearance, triangular face, arachnodactyly, lipodystrophy, thin skin, hepatomegaly, delayed bone age, hypoplastic labia majora, and clitoral hypertrophy ([PMID:35023948]). Both variants are absent from population databases and affect conserved residues in the ATP-binding domain. Segregation confirmed autosomal recessive inheritance, though no additional affected relatives were reported.

Supportive functional evidence includes a zebrafish cdc6 hypomorphic mutant (cdc6tsu21cd) that recapitulates MGS-like short stature and growth retardation, and overexpression of human CDC6(T323R) partially rescues embryonic lethality, indicating a hypomorphic mechanism ([PMID:28985365]). Yeast mutagenesis of conserved ATP-binding lysine residues similarly impairs pre-RC assembly and DNA replication origin licensing. These data collectively support that loss-of-function CDC6 variants underlie MGS5. Key take-home: CDC6 loss-of-function variants cause autosomal recessive Meier-Gorlin syndrome 5 through defective origin licensing, informing diagnostic gene panels and genetic counseling.

References

• The application of clinical genetics • 2022 • Novel Compound Heterozygous Variants in the CDC6 Gene in a Russian Patient with Meier-Gorlin Syndrome PMID:35023948
• Human molecular genetics • 2017 • Zebrafish cdc6 hypomorphic mutation causes Meier-Gorlin syndrome-like phenotype PMID:28985365

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