Abstract
Loss-of-function variants in CHAMP1 were recently described as cause of a neurodevelopmental disorder characterized by intellectual disability (ID), autism, and distinctive facial characteristics. By exome sequencing (ES), we identified a truncating variant in CHAMP1, c.1858A > T (p.Lys620*), in a patient who exhibited a similar phenotype of severe ID and dysmorphisms. Whether haploinsufficiency or a dominant negative effect is the underlying pathomechanism in these cases is a question that still needs to be addressed. By array-CGH, we detected a 194 kb deletion in 13q34 encompassing CHAMP1, CDC16 and UPF3, in another patient who presented with borderline neurodevelopmental impairment and with no dysmorphisms. In a further patient suffering from early onset refractory seizures, we detected by ES a missense variant in CHAMP1, c.67 G > A (p.Gly23Ser). Genomic abnormalities were all de novo in our patients. We reviewed the clinical and the genetic data of patients reported in the literature with: loss-of-function variants in CHAMP1 (total 40); chromosome 13q34 deletions ranging from 1.1 to 4 Mb (total 7) and of the unique patient with a missense variant. We could infer that loss-of-function variants in CHAMP1 cause a homogeneous phenotype with severe ID, autism spectrum disorders (ASD) and highly distinctive facial characteristics through a dominant negative effect. CHAMP1 haploinsufficiency results in borderline ID with negligible consequences on the quality of life. Missense variants give rise to a severe epileptic encephalopathy through gain-of-function mechanism, most likely. We tentatively define for the first time distinct categories among the CHAMP1-related disorder on the basis of pathomechanisms.
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Data availability
All data relevant to the study are included in the article. The three CHAMP1 variants described in this study were submitted to the ClinVar Database (https://www.ncbi.nlm.nih.gov/clinvar/) and received the following codes: SCV002817425 (Accession: VCV001878430.1, Variation ID: 1878430), SCV002766597 (Accession: VCV001806448.1, Variation ID: 1806448), and SCV002765127 (Accession: VCV000981896.2, Variation ID: 981896).
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Acknowledgements
We thank Giovanni Neri, for participating to the discussion. We are grateful to the families for their support.
Funding
This study was supported by Fondazione Telethon (Italy) (GSP15001- Telethon Undiagnosed Program). This project has also received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 779257 (Solve‐RD): “SOLVE RD”.
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SA is involved in manuscript writing and literature revision. GM collaborated in manuscript writing and literature revision and performed bioinformatics analyses. DO performed array-CGH. SF performed cDNA analysis. FG, MS, FR and VC contributed patient cases and contributed to manuscript revision. EP contributed in literature revision and in created tables and patient figures. TUDP performed ES analysis. VN performed interpretation and validation of ES results. MZ was responsible for the study design and supervised all the activities.
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All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. They were specifically approved by the Department of Life Sciences and Public Health of Catholic University of Roma, Italy, with protocol nr. DIPUVSP-PD-10-2231.
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Amenta, S., Marangi, G., Orteschi, D. et al. CHAMP1-related disorders: pathomechanisms triggered by different genomic alterations define distinct nosological categories. Eur J Hum Genet 31, 648–653 (2023). https://doi.org/10.1038/s41431-023-01305-z
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DOI: https://doi.org/10.1038/s41431-023-01305-z
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