Evidence map›Paper›PMID 41962535›Full record

ArticleAmerican journal of human genetics2026

Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism.

Debora Tibbe, Marie Ronja Vogt, Tess Holling, Lea Dewi Schlieben, Fanny Kortüm, Moneef Shoukier, Christoph Bagowski, Felix Distelmaier, Luisa Averdunk, Alexej Knaus and 33 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0citing papers in PubMed
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1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

43 authors.

Debora TibbeInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Marie Ronja VogtDepartment of Radiotherapy & Radiation Oncology, Hubertus Wald Tumor Center - University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Tess HollingInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Lea Dewi SchliebenInstitute of Human Genetics, School of Medicine and Health, Technical University Munich, 81675 Munich, Germany.
Fanny KortümInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Moneef ShoukierEurofins Humangenetik und Pränatal-Medizin MVZ GmbH, 80639 Munich, Germany.
Christoph BagowskiEurofins Humangenetik und Pränatal-Medizin MVZ GmbH, 80639 Munich, Germany.
Felix DistelmaierDepartment of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
Luisa AverdunkDepartment of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
Alexej KnausInstitute for Genomic Statistics and Bioinformatics, University Hospital Bonn, 53113 Bonn, Germany.
Peter KrawitzInstitute for Genomic Statistics and Bioinformatics, University Hospital Bonn, 53113 Bonn, Germany.
Alma KuechlerInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.
Elke LainkaUniversity Children's Hospital Essen, Pediatric Gastroenterology, Rheumatology, Transplant Medicine, 45147 Essen, Germany.
Amelie StalkeDepartment of Human Genetics, Hannover Medical School, 30625 Hannover, Germany.
Sandra von HardenbergDepartment of Human Genetics, Hannover Medical School, 30625 Hannover, Germany.
Bernd AuberDepartment of Human Genetics, Hannover Medical School, 30625 Hannover, Germany.
Eva-Doreen PfisterDepartment for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany.
Bruno ReversadeLaboratory of Human Genetics & Therapeutics, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia.
Anthony SabbaghUniversite Saint Joseph de Beyrouth, Faculte de Medecine Damascus, Beirut 1107-2180, Lebanon.
Aida M Bertoli-AvellaCENTOGENE GmbH, 18055 Rostock, Germany.
Salem AlawbathaniCENTOGENE GmbH, 18055 Rostock, Germany.
Elizabeth E PalmerDiscipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, NSW 2031, Australia.
Manisha ChauhanCentre for Clinical Genetics, Sydney Children's Hospitals Network, Randwick, Sydney, NSW 2031, Australia.
Rocio RiusCentre 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.
Yoonji KimDiscipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, NSW 2031, Australia.
Australian Undiagnosed Diseases Network (UDN-Aus)Australian Undiagnosed Diseases Network (UDN-Aus), Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
Dzhoy PapingiInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Deborah BartholdiINSELSPITAL, University Hospital Bern Department of Human Genetics, 3010 Bern, Switzerland.
Dominique BraunINSELSPITAL, University Hospital Bern Department of Human Genetics, 3010 Bern, Switzerland.
Oliver MaierDepartment of Child Neurology, Developmental Medicine and Rehabilitation, Children's Hospital of Eastern Switzerland, 9006 St. Gallen, Switzerland.
April DinwiddieCeGaT, 72076 Tübingen, Germany.
Elisabeth Steichen-GersdorfDepartment of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Andreas R JaneckeDepartment of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria; Institute of Human Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Anatoly TiulpakovDepartment of Endocrine Genetics, Research Centre for Medical Genetics, Moscow 115522, Russian Federation.
Nikolay ZernovBiotech Campus LLC, Moscow 117997, Russian Federation.
Maria Izabel ArismendiGenetic Endocrinology Unit (LIM25), Endocrinology Division, Faculdade de Medicinada Universidade de São Paulo (HC-FMUSP), São Paulo 01246-903, Brazil.
Alexander A L JorgeGenetic Endocrinology Unit (LIM25), Endocrinology Division, Faculdade de Medicinada Universidade de São Paulo (HC-FMUSP), São Paulo 01246-903, Brazil.
Himanshu GoelHunter Genetics, Waratah, NSW 2298, Australia; University of Newcastle, Callaghan, NSW 2308, Australia.
Lauren DreyerGenetic Health Western Australia, Perth, WA 6008, Australia.
Lily LoughmanGenetic Health Western Australia, Perth, WA 6008, Australia.
Holger ProkischInstitute 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.
Kerstin BorgmannDepartment of Radiotherapy & Radiation Oncology, Hubertus Wald Tumor Center - University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Kerstin KutscheInstitute 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.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

DNA-Binding ProteinsDwarfismMicrocephalyAllelesCell ProliferationChildChild, PreschoolDNA DamageDNA ReplicationFemaleFibroblastsHumansMaleReplisomesDNA-Binding ProteinsReplisomescheckpointDNA replicationDNA replication stressgenomic integrityhypomorphic variantsMeier-Gorlin syndromemicrocephalyreplication forksister chromatid cohesionWDHD1

Identifiers

PMID41962535
PMCPMC13277691

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