338: WDHD1 and Microcephalic Primordial Dwarfism

Tibbe D et al., The American Journal of Human Genetics - This study identifies bi-allelic hypomorphic WDHD1 variants in 17 subjects with a clinical spectrum from fetal lethality to microcephalic primordial dwarfism and characterizes cellular defects in patient-derived cells linked to replisome dysfunction. Key terms: WDHD1, microcephalic primordial dwarfism, replication stress, sister chromatid cohesion, splicing variants.

Study Highlights:
Researchers found bi-allelic WDHD1 variants in 17 subjects presenting with intrauterine growth retardation, microcephaly and a spectrum of organ abnormalities including neonatal acute liver failure. Several intronic variants cause aberrant splicing and markedly reduced WDHD1 protein levels in fibroblasts. Subject-derived cells showed slowed replication fork progression, impaired G1-to-S transition, increased spontaneous DNA damage, abnormal nuclear morphology, and elevated premature sister chromatid separation, supporting a role for WDHD1 in replisome stability and cohesion.

Conclusion:
Hypomorphic bi-allelic WDHD1 variants cause an autosomal recessive microcephalic primordial dwarfism spectrum by reducing WDHD1 protein and impairing replication fork stability, genome integrity, and sister chromatid cohesion, establishing WDHD1 as essential for normal human growth and development.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism

First author:
Tibbe D

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.03.010

Reference:
Tibbe D., Vogt M.R., Holling T., et al. Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism. The American Journal of Human Genetics. 2026. https://doi.org/10.1016/j.ajhg.2026.03.010

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/wdhd1-microcephalic-primordial-dwarfism

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-10.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's coverage of WDHD1 function as replisome scaffold; intronic WDHD1 variants and splicing; DNA fiber assay and replication fork dynamics; γH2AX signaling; nuclear morphology; PCS; and liver pathology in MPD.
- transcript topics: WDHD1 as replisome scaffold; intronic WDHD1 variants and splicing; DNA fiber assay and replication fork speed; γH2AX DNA damage signaling; nuclear morphology and lamin B1; premature sister chromatid separation (PCS)

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- 17 subjects from 14 families with bi-allelic WDHD1 variants and MPD spectrum
- intronic WDHD1 variants cause aberrant splicing and markedly reduced WDHD1 protein levels in patient-derived cells
- WDHD1 acts as replisome scaffolding to stabilize replication forks and maintain genome integrity
- replication fork progression is slowed and there is increased sp...