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


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.

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


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


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

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Authors and Affiliations



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.

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Correspondence to Irene Bottillo.

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The authors declare no competing interests.

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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).

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