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Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism

Debora Tibbe1, Marie Ronja Vogt2, Tess Holling1

  • 1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

American Journal of Human Genetics
|April 10, 2026
PubMed

Insights

Bi-allelic hypomorphic variants in WDHD1 cause microcephalic primordial dwarfism (MPD) and liver failure. This highlights WDHD1

Area of Science:

  • Genetics and Genomics
  • Molecular Biology
  • Cell Biology

Background:

  • Microcephalic primordial dwarfism (MPD) is linked to pathogenic variants in genes encoding replisome components.
  • The replisome is crucial for DNA replication, genome integrity, and cell proliferation.

Purpose of the Study:

  • To identify the genetic cause of MPD with additional abnormalities in affected individuals.
  • To investigate the functional consequences of WDHD1 variants on DNA replication and genome stability.

Main Methods:

  • Genetic analysis of 17 subjects from 14 families.
  • Analysis of WDHD1 gene variants, pre-mRNA splicing, and protein levels.
  • Cell biology studies using subject-derived fibroblasts to assess replication fork speed, DNA damage, cell cycle progression, and nuclear morphology.

Main Results:

  • Bi-allelic hypomorphic variants in WDHD1 were identified as a cause of MPD with acute liver failure and other developmental abnormalities.
  • WDHD1 variants led to aberrant splicing and reduced protein levels, resulting in impaired replication fork speed, DNA damage, and cell cycle defects.
  • Subject fibroblasts exhibited reduced proliferation, abnormal nuclear morphology (micronuclei, multilobed/enlarged nuclei), and premature sister chromatid separation.

Conclusions:

  • WDHD1 variants are a novel cause of MPD and associated severe clinical manifestations.
  • WDHD1 is essential for human growth and development, playing critical roles in DNA replication, fork stability, and sister chromatid cohesion.
  • These findings underscore the importance of WDHD1 in maintaining genome integrity.
Keywords:
DNA replicationDNA replication stressMeier-Gorlin syndromeWDHD1checkpointgenomic integrityhypomorphic variantsmicrocephalyreplication forksister chromatid cohesion

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