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European journal of human genetics : EJHG
Mar 20, 2025;

XRCC4-related microcephalic primordial dwarfism: description of a clinical series of 7 cases, phenotype expansion and new diagnostic approaches.

Silvestre Cuinat, Nicolas Chatron, Florence Petit, Perrine Brunelle, Etienne Dincuff, Marion Aubert Mucca, Eric Bieth, Ariane Schmetz, Harald Rieder, Bernd Wollnik, Silke Kaulfu��, G��khan Yigit, Colina McKeown, Tim Savage, Meghan R Mulligan, Louise S Bicknell, Nicole Corsten-Janssen, Patrick Edery, Gaetan Lesca, Jean-Pierre de Villartay, Audrey Putoux
Author Information
  1. Silvestre Cuinat: Hospices Civils de Lyon, Service de G��n��tique, Centre Lab��lis�� Anomalies du D��veloppement CLAD Sud-Est, Lyon, France. silvestre.cuinat@inserm.fr. ORCID
  2. Nicolas Chatron: Hospices Civils de Lyon, Service de G��n��tique, Centre Lab��lis�� Anomalies du D��veloppement CLAD Sud-Est, Lyon, France. ORCID
  3. Florence Petit: Univ. Lille, CHU Lille, ULR 7364 - RADEME, F-59000, Lille, France.
  4. Perrine Brunelle: Univ. Lille, CHU Lille, ULR 7364 - RADEME, F-59000, Lille, France. ORCID
  5. Etienne Dincuff: Laboratory �� Genome Dynamics in the Immune System ��, INSERM UMR 1163, DGSI, Equipe labellis��e La Ligue Nationale Contre le Cancer, Institut Imagine, Universit�� Paris Descartes Sorbonne Paris Cit��, 75015, Paris, France.
  6. Marion Aubert Mucca: Service de G��n��tique M��dicale, H��pital Purpan, CHU, 31059, Toulouse, France. ORCID
  7. Eric Bieth: Service de G��n��tique M��dicale, H��pital Purpan, CHU, 31059, Toulouse, France.
  8. Ariane Schmetz: Institute of Human Genetics, Medical Faculty and University Hospital D��sseldorf, Heinrich Heine University, D��sseldorf, Germany. ORCID
  9. Harald Rieder: Institute of Human Genetics, Medical Faculty and University Hospital D��sseldorf, Heinrich Heine University, D��sseldorf, Germany.
  10. Bernd Wollnik: Institute of Human Genetics, University Medical Center G��ttingen, G��ttingen, Germany. ORCID
  11. Silke Kaulfu��: Institute of Human Genetics, University Medical Center G��ttingen, G��ttingen, Germany. ORCID
  12. G��khan Yigit: Institute of Human Genetics, University Medical Center G��ttingen, G��ttingen, Germany. ORCID
  13. Colina McKeown: Genetic Health Service, Wellington Children's Hospital, Wellington, New Zealand.
  14. Tim Savage: General Pediatrics, Diabetes and Endocrinology, Wellington Children's Hospital, Wellington, New Zealand.
  15. Meghan R Mulligan: Department of Biochemistry, University of Otago, Dunedin, New Zealand. ORCID
  16. Louise S Bicknell: Department of Biochemistry, University of Otago, Dunedin, New Zealand. ORCID
  17. Nicole Corsten-Janssen: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. ORCID
  18. Patrick Edery: Hospices Civils de Lyon, Service de G��n��tique, Centre Lab��lis�� Anomalies du D��veloppement CLAD Sud-Est, Lyon, France.
  19. Gaetan Lesca: Hospices Civils de Lyon, Service de G��n��tique, Centre Lab��lis�� Anomalies du D��veloppement CLAD Sud-Est, Lyon, France. ORCID
  20. Jean-Pierre de Villartay: Laboratory �� Genome Dynamics in the Immune System ��, INSERM UMR 1163, DGSI, Equipe labellis��e La Ligue Nationale Contre le Cancer, Institut Imagine, Universit�� Paris Descartes Sorbonne Paris Cit��, 75015, Paris, France.
  21. Audrey Putoux: Hospices Civils de Lyon, Service de G��n��tique, Centre Lab��lis�� Anomalies du D��veloppement CLAD Sud-Est, Lyon, France. audrey.putoux@chu-lyon.fr. ORCID
PMID: 40114033 DOI: 10.1038/s41431-025-01821-0

Abstract

The non-homologous end joining (NHEJ) pathway is essential to repair DNA double-strand breaks. XRCC4 acts as a stabilizer of the DNA ligase LIG4 in the NHEJ process. In humans, XRCC4 pathogenic variants are responsible for a microcephalic primordial dwarfism syndrome (MPD). Currently, 17 patients have been reported with XRCC4-related MPD and we report 7 new patients from 6 different families, including one fetus. The patients present with short stature, severe microcephaly, neurodevelopmental disorder and additional features, such as transient increase in nuchal translucency, congenital glaucoma, thumb anomalies, hepatic steatosis, seizures, essential tremor and oligodontia which have not been previously described. Hyper- and hypopigmented skin macules, dermatofibrosarcoma, mandibular osteoid osteoma and pancytopenia are also new features, reminiscent of cancer susceptibility syndromes. Functional studies were performed on two patients carrying the known pathogenic p.(Trp43Arg) variant in homozygous state, using a fast, cost-effective and non-invasive approach on PBMCs: (1) Survival analyses after ionizing radiation confirm important radiosensitivity. (2) Flow cytometry showed the lack of TCR-Va7+ T-lymphocytes, suggesting recombination defect of V(D)J coding segments. (3) This was confirmed by multiplexed RT-PCR (PROMIDIS�� biomarker), analyzing the diversity of V(D)J coding segments in a subset of the TCR�� repertoire. We therefore extend the phenotype of XRCC4-related MPD and suggest a combination of three functional assays, based on radiosensitivity and V(D)J recombination defect, to improve the interpretation of XRCC4 variants in fast, cost-effective and non-invasive manner. These findings will improve the diagnosis, genetic counselling, follow-up and management of these patients.

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