GINS3 – Meier-Gorlin Syndrome

Meier-Gorlin syndrome (MGORS) is an autosomal recessive disorder characterized by short stature, microtia, and patellar hypoplasia, caused by pathogenic variants in DNA replication initiation factors. Recent studies have implicated biallelic variants in GINS3 (HGNC:25851) as a novel genetic cause of MGORS ([PMID:35603789]). The phenotype overlaps canonical features of MGORS, confirming the critical role of the GINS complex in human development.

Initial multi-patient analyses identified 7 individuals from 5 unrelated families harboring hypomorphic GINS3 variants affecting Asp24 (p.Asp24Gly, p.Asp24Asn) and Arg82 (p.Arg82Gln), all presenting MGORS features ([PMID:35603789]). Follow-up case reports described two additional probands homozygous for p.Asp24Asn and p.Ile25Phe with classic short stature, microtia, and patellar hypoplasia ([PMID:38773883]). In total, 9 probands across 7 families exhibit autosomal recessive inheritance without reported affected relatives beyond the index cases.

The variant spectrum is dominated by missense changes at conserved residues: p.Asp24Gly, p.Asp24Asn, p.Ile25Phe, and p.Arg82Gln. No predicted loss-of-function alleles have been reported, consistent with an essential role for GINS3 in replication. A recurrent D24Asn allele appears in multiple pedigrees, suggesting a possible founder or mutational hotspot effect.

Functional assays in yeast demonstrate that substitution of the orthologous residue (Val9Phe) compromises S phase progression, reduces protein stability, and increases sensitivity to hydroxyurea and thermal stress ([PMID:35603789]). Human fibroblasts expressing MGORS-associated variants accumulate in S phase with reduced proliferative capacity, confirming partial loss of helicase activity.

Mouse models homozygous for D24 variants exhibit intrauterine growth retardation, embryonic lethality, and accelerated cellular senescence in fibroblasts, recapitulating the human growth defect and viability threshold ([PMID:35603789]). Rescue experiments using a humanized Psf3 Val9Ile allele restore viability in yeast, underscoring the pathogenic mechanism.

The convergence of genetic and experimental evidence—9 probands with biallelic GINS3 variants and concordant in vitro and in vivo functional models—supports a Strong clinical validity classification. GINS3 should be incorporated into diagnostic gene panels for MGORS. Key take-home: Hypomorphic GINS3 missense variants impair DNA replication and cause classic Meier-Gorlin syndrome, informing molecular diagnosis and patient management.

References

• JCI Insight • 2022 • Hypomorphic GINS3 variants alter DNA replication and cause Meier-Gorlin syndrome. PMID:35603789
• Clinical Genetics • 2024 • Functional studies in yeast confirm the pathogenicity of a new GINS3 Meier-Gorlin syndrome variant. PMID:38773883

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