CDT1 – Meier-Gorlin syndrome

Meier-Gorlin syndrome (MGORS) is an autosomal recessive primordial dwarfism characterized by microtia, patellar aplasia or hypoplasia, and short stature. Pathogenic variants in genes encoding pre-replication complex components, including CDT1, underlie this disorder (PMID:21358632). CDT1 encodes a DNA replication licensing factor essential for MCM complex loading, and biallelic CDT1 mutations account for a significant fraction of MGORS cases, demonstrating locus heterogeneity and a consistent clinical triad.

Genetic evidence for CDT1 involvement includes 45 individuals across multiple cohorts, with 35 carrying biallelic CDT1 variants (PMID:22333897). Inheritance is autosomal recessive, and multiple families exhibit segregation of compound heterozygous or homozygous variants. A recent report identified the first homozygous intronic splice-altering variant c.352-30A>C in CDT1, confirming pathogenicity via minigene assays (PMID:39789585).

The CDT1 variant spectrum in MGORS comprises missense, loss-of-function, splice, and deep intronic alleles. A novel deep intronic variant c.352-30A>C leads to exon 3 skipping and severe growth retardation (PMID:39789585). Numerous compound heterozygous missense variants have been described, often clustering at critical MCM-interaction interfaces (PMID:22333897). No recurrent founder allele has been established.

Functional studies confirm the pathogenic mechanism as impaired replication licensing. Minigene constructs for c.352-30A>C demonstrate exon 3 exclusion in vitro, validating aberrant splicing (PMID:39789585). Additional biochemical assays of MGORS-associated Cdt1 missense variants show reduced MCM loading efficiency and altered cyclin A/CDK regulation, linking variant position to licensing activity defects (PMID:30281379).

The clinical phenotype extends beyond the core triad: growth hormone (GH) therapy increased growth velocity from 4.0 cm/y to 6.2 cm/y in a child with homozygous c.352-30A>C, suggesting potential benefit in select patients (PMID:39789585). An adult female with compound in-frame deletion and deep intronic branch-point variant achieved successful pregnancies complicated by uterine abnormalities and postpartum hemorrhage, expanding the lifespan and reproductive profile of MGORS (PMID:33338304).

In summary, CDT1 is firmly established as an MGORS gene with strong clinical validity, supported by over 35 unrelated probands, segregation in multiple families, and concordant functional data. The predominant mechanism is loss of replication licensing via splicing or missense disruption at key protein interfaces. Screening of CDT1 should be integral to MGORS diagnostic panels, and GH therapy may be considered for growth optimization in patients with normal IGF-1 levels.

References

• Nature Genetics • 2011 • Mutations in the pre-replication complex cause Meier-Gorlin syndrome. PMID:21358632
• European Journal of Human Genetics • 2012 • Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis. PMID:22333897
• Orphanet Journal of Rare Diseases • 2024 • A novel homozygous intronic variant in CDT1 that alters splicing causes Meier-Gorlin syndrome, and a review of published mutations and growth hormone treatments. PMID:39789585
• American Journal of Medical Genetics Part A • 2021 • Successful pregnancies in an adult with Meier-Gorlin syndrome harboring biallelic CDT1 variants. PMID:33338304
• Molecular Biology of the Cell • 2018 • Cdt1 variants reveal unanticipated aspects of interactions with cyclin/CDK and MCM important for normal genome replication. PMID:30281379

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