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Two unrelated cases with biallelic CHEK2 variants:a novel condition with constitutional chromosomal instability?

European Journal of Human Genetics (2022)Cite this article

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Abstract

Constitutional heterozygous mutations in CHEK2 gene have been associated with hereditary cancer risk. To date, only a few homozygous CHEK2 mutations have been reported in families with cancer susceptibility. Here, we report two unrelated individuals with a personal and familial cancer history in whom biallelic CHEK2 alterations were identified. The first case resulted homozygous for the CHEK2 c.793-1 G > A (p.Asp265Thrfs*10) variant, and the second one was found to be compound heterozygous for the c.1100delC (p.Thr367Metfs*15) and the c.1312 G > T (p.Asp438Tyr) variants. Multiple cytogenetic anomalies were demonstrated on peripheral lymphocytes of both patients. A literature revision showed that a single other CHEK2 homozygous variant was previously associated to a constitutional randomly occurring multi-translocation karyotype from peripheral blood in humans. We hypothesize that, at least some biallelic CHEK2 mutations might be associated with a novel disorder, further expanding the group of chromosome instability syndromes. Additional studies on larger cohorts are needed to confirm if chromosomal instability could represent a marker for CHEK2 constitutionally mutated recessive genotypes, and to investigate the cancer risk and the occurrence of other anomalies typically observed in chromosome instability syndromes.

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Fig. 1: Pedigree of family A and family B.

Data availability

The data generated and analysed during this study can be found within the published article.

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Acknowledgements

The authors thank all the patients for participating in this study.

Funding

This study was funded by the Experimental Medicine Department, Sapienza University of Rome.

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Authors and Affiliations

  1. Division of Medical Genetics, Department of Experimental Medicine, San Camillo-Forlanini Hospital, Sapienza University, Rome, Italy

    Irene Bottillo, Emanuele Savino, Silvia Majore, Claudia Mulargia, Michele Valiante, Alessandro Ferraris, Maria Pia Ciccone, Francesca Brusco, Barbara Grammatico, Gianluca Di Giacomo, Simone Bargiacchi, Daniela D’Angelantonio & Paola Grammatico

  2. Breast Oncology Unit, San Camillo-Forlanini Hospital, Rome, Italy

    Valentina Rossi & Francesca Svegliati

Authors
  1. Irene Bottillo
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  2. Emanuele Savino
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Contributions

BI: conception of the study and drafting the manuscript; SE: acquisition of data and drafting the manuscript; MS and AF: clinical genetic evaluation and revising the manuscript; MC: acquisition of data; VM: clinical genetic evaluation and revising the manuscript; FA: genetic counselling; RV: clinical assessment; SF: clinical assessment; CMP: analysis and interpretation of data; BF: analysis and interpretation of data; GB: acquisition of data; DGG: acquisition of data; BS: analysis and interpretation of data; DD: analysis and interpretation of data; GP: revising the article critically for important intellectual content.

Corresponding author

Correspondence to Irene Bottillo.

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Competing interests

The authors declare no competing interests.

Ethics approval

Informed consent was obtained from all subjects, and study procedures were compliant with the revised Helsinki Declaration of 2000. The study, part of a research project about genetic disorders, was approved by the San Camillo Forlanini Hospital Ethics Board.

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Bottillo, I., Savino, E., Majore, S. et al. Two unrelated cases with biallelic CHEK2 variants:a novel condition with constitutional chromosomal instability?. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01270-z

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