Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism

May 07, 2026

Debora Tibbe 1, Marie Ronja Vogt 2, Tess Holling 1, Lea Dewi Schlieben 3, Fanny Kortüm 1, Moneef Shoukier 4, Christoph Bagowski 4, Felix Distelmaier 5, Luisa Averdunk 5, Alexej Knaus 6, Peter Krawitz 6, Alma Kuechler 7, Elke Lainka 8, Amelie Stalke 9, Sandra von Hardenberg 9, Bernd Auber 9, Eva-Doreen Pfister 10, Bruno Reversade 11, Anthony Sabbagh 12, Aida M Bertoli-Avella 13, Salem Alawbathani 13, Elizabeth E Palmer 14, Manisha Chauhan 15, Rocio Rius 16, Yoonji Kim 14; Australian Undiagnosed Diseases Network (UDN-Aus) 17; Dzhoy Papingi 1, Deborah Bartholdi 18, Dominique Braun 18, Oliver Maier 19, April Dinwiddie 20, Elisabeth Steichen-Gersdorf 21, Andreas R Janecke 22, Anatoly Tiulpakov 23, Nikolay Zernov 24, Maria Izabel Arismendi 25, Alexander A L Jorge 25, Himanshu Goel 26, Lauren Dreyer 27, Lily Loughman 27, Holger Prokisch 28, Kerstin Borgmann 2, Kerstin Kutsche 29

Abstract

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.

Keywords: DNA replication; DNA replication stress; Meier-Gorlin syndrome; WDHD1; checkpoint; genomic integrity; hypomorphic variants; microcephaly; replication fork; sister chromatid cohesion.

  1. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  2. Department of Radiotherapy & Radiation Oncology, Hubertus Wald Tumor Center – University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  3. Institute of Human Genetics, School of Medicine and Health, Technical University Munich, 81675 Munich, Germany.
  4. Eurofins Humangenetik und Pränatal-Medizin MVZ GmbH, 80639 Munich, Germany.
  5. Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
  6. Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, 53113 Bonn, Germany.
  7. Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.
  8. University Children’s Hospital Essen, Pediatric Gastroenterology, Rheumatology, Transplant Medicine, 45147 Essen, Germany.
  9. Department of Human Genetics, Hannover Medical School, 30625 Hannover, Germany.
  10. Department for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany.
  11. Laboratory of Human Genetics & Therapeutics, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia.
  12. Universite Saint Joseph de Beyrouth, Faculte de Medecine Damascus, Beirut 1107-2180, Lebanon.
  13. CENTOGENE GmbH, 18055 Rostock, Germany.
  14. Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, NSW 2031, Australia.
  15. Centre for Clinical Genetics, Sydney Children’s Hospitals Network, Randwick, Sydney, NSW 2031, Australia.
  16. Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, NSW 2031, Australia; Centre for Population Genomics Murdoch Children’s Research Institute, Melbourne, VIC 3051, Australia.
  17. Australian Undiagnosed Diseases Network (UDN-Aus), Murdoch Children’s Research Institute, Melbourne, VIC 3052, Australia.
  18. INSELSPITAL, University Hospital Bern Department of Human Genetics, 3010 Bern, Switzerland.
  19. Department of Child Neurology, Developmental Medicine and Rehabilitation, Children’s Hospital of Eastern Switzerland, 9006 St. Gallen, Switzerland.
  20. CeGaT, 72076 Tübingen, Germany.
  21. Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria.
  22. Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria; Institute of Human Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
  23. Department of Endocrine Genetics, Research Centre for Medical Genetics, Moscow 115522, Russian Federation.
  24. Biotech Campus LLC, Moscow 117997, Russian Federation.
  25. Genetic Endocrinology Unit (LIM25), Endocrinology Division, Faculdade de Medicinada Universidade de São Paulo (HC-FMUSP), São Paulo 01246-903, Brazil.
  26. Hunter Genetics, Waratah, NSW 2298, Australia; University of Newcastle, Callaghan, NSW 2308, Australia.
  27. Genetic Health Western Australia, Perth, WA 6008, Australia.
  28. Institute of Human Genetics, School of Medicine and Health, Technical University Munich, 81675 Munich, Germany; Institute of Neurogenomics, Computational Health, Helmholtz Zentrum München, 85764 Munich, Germany; German Center for Child and Adolescent Health (DZKJ), Partner Site Munich, 80337 Munich, Germany.
  29. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; German Center for Child and Adolescent Health (DZKJ), Partner Site Hamburg, 20251 Hamburg, Germany. Electronic address: kkutsche@uke.de.