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

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 (PROMIDISα biomarker), analyzing the diversity of V(D)J coding segments in a subset of the TCRα 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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Journal
European Journal of Human Genetics
Published
2025-03-20
DOI
https://doi.org/10.1038/s41431-025-01821-0
Citations
2
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
1.61

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article

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

Colina McKeown, Thomas F. Savage, Harald E. Rieder, Ariane Schmetz et al.
2 citations
European Journal of Human Genetics
DNA Repair Mechanisms
1.61
article

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

Colina McKeown, Thomas F. Savage, Harald E. Rieder, Ariane Schmetz, Audrey Putoux, Silke Kaulfuß, Silvestre Cuinat, Nicole Corsten‐Janssen, Louise S. Bicknell, Gaëtan Lesca, Florence Petit, Perrine Brunelle, Marion Aubert‐Mucca, Bernd Wollnik, Jean‐Pierre de Villartay, Patrick Edery, Nicolas Chatron, Meghan R. Mulligan, Éric Bieth, Gökhan Yiğit, Etienne Dincuff
article en
2 citations

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 (PROMIDISα biomarker), analyzing the diversity of V(D)J coding segments in a subset of the TCRα 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.

European Journal of Human GeneticsVol. 33(7)
Université Claude Bernard Lyon 1 (FR), Délégation Paris 5 (FR), Centre National de la Recherche Scientifique (FR), University Medical Center Groningen (NL), Inserm (FR), University of Groningen (NL), Université Paris Cité (FR), Université de Lille (FR), Wellington Hospital (NZ), Centre Hospitalier Universitaire de Lille (FR), Düsseldorf University Hospital (DE), Sorbonne Paris Cité (FR), Centre de Recherche en Neurosciences de Lyon (FR), La Ligue Contre le Cancer (FR), Hospices Civils de Lyon (FR), Universitätsmedizin Göttingen (DE), Institut NeuroMyoGène (FR), German Centre for Cardiovascular Research (DE), Nanoscale Microscopy and Molecular Physiology of the Brain Cluster of Excellence 171 — DFG Research Center 103 (DE), Hôpital Purpan (FR), Heinrich Heine University Düsseldorf (DE), University of Göttingen (DE), University of Otago (NZ)
European Commission, Neurological Foundation of New Zealand, Hospices Civils de Lyon
Good health and well-being
Openalex Percentile: Top 18%
DNA Repair Mechanisms
1.61
DOIOpen Access PDFOpenAlex
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