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Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism.

American journal of human genetics

Authors: Debora Tibbe, Marie Ronja Vogt, Tess Holling, Lea Dewi Schlieben, Fanny Kortüm, Moneef Shoukier, Christoph Bagowski, Felix Distelmaier, Luisa Averdunk, Alexej Knaus, Peter Krawitz, Alma Kuechler, Elke Lainka, Amelie Stalke, Sandra von Hardenberg, Bernd Auber, Eva-Doreen Pfister, Bruno Reversade, Anthony Sabbagh, Aida M Bertoli-Avella, Salem Alawbathani, Elizabeth E Palmer, Manisha Chauhan, Rocio Rius, Yoonji Kim, Dzhoy Papingi, Deborah Bartholdi, Dominique Braun, Oliver Maier, April Dinwiddie, Elisabeth Steichen-Gersdorf, Andreas R Janecke, Anatoly Tiulpakov, Nikolay Zernov, Maria Izabel Arismendi, Alexander A L Jorge, Himanshu Goel, Lauren Dreyer, Lily Loughman, Holger Prokisch, Kerstin Borgmann, Kerstin Kutsche

DNA replication is carried out by the replisome and is essential for maintaining genome integrity and cell proliferation. Pathogenic variants in genes encoding various replisome components cause microcephalic primordial dwarfism (MPD), characterized by growth retardation, microcephaly, and developmental abnormalities. Here, we report bi-allelic hypomorphic variants in WDHD1 as a cause of MPD with a broad spectrum of additional abnormalities, including acute liver failure, in 17 subjects from 14 families. WDHD1 encodes a replisome scaffolding protein (also known as AND-1 and Ctf4), which is essential for replisome assembly, replication fork stability, and sister chromatid cohesion. We found aberrant splicing of WDHD1 pre-mRNAs for all intronic variants tested and markedly reduced WDHD1 protein levels in subject-derived fibroblasts. Fibroblasts with bi-allelic WDHD1 variants showed globally reduced replication fork speed and impaired replication control, accompanied by spontaneous DNA damage and a G1-to-S transition defect. Using various cell biology approaches, we show that subject fibroblasts displayed reduced proliferation, abnormal nuclear morphology, including micronuclei, multilobed, and enlarged nuclei, as well as an increased number of metaphases with premature sister chromatid separation. Together, our findings establish WDHD1 as a protein required for normal organismal growth and development in humans and underscore its multiple functions in maintaining genome integrity.

Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.

PMID: 41962535

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