First description of revertant mosaicism in familial platelet disorder with predisposition to acute myelogenous leukemia: correlation with the clinical phenotype

Glembotsky, Ana Claudia; Oyarzún, Cecilia Paola Marin; Luca, Geraldine De; Marzac, Christophe; Auger, Nathalie; Goette, Nora Paula; Marta, Rosana Fernanda; Raslová, Hana; Heller, Paula G.

doi:10.3324/haematol.2020.253070

Cited by 8 publications

(4 citation statements)

References 16 publications

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“…The diagnosis of mosaicism remains an unmet medical need in the routine practice of genetic laboratories ( 7 , 8 , 9 , 10 , 11 ). NGS offers the possibility of detecting mosaic variants using DNA from blood ( 7 , 8 , 14 , 16 , 17 ).…”

Section: Discussionmentioning

confidence: 99%

“…Mosaicism can explain some of these unresolved cases. Mosaicism has been described in several inherited tumor syndromes and corresponds to the spontaneous acquisition of a genetic variant during cell division during post-zygotic embryonic development ( 7 , 8 , 9 , 10 , 11 ). Mosaicism thus results in a fetus composed of a variable proportion of mutated cells, depending on how early and in which cell lines the variant occurs.…”

Section: Introductionmentioning

confidence: 99%

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Systematic detection of mosaicism by using digital NGS reveals three new MEN1 mosaicisms

Lagarde

Mougel

Coppins

et al. 2022

Endocrine Connections

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Purpose: Mosaicism is a feature of several inherited tumor syndromes. Only few cases of mosaicism in Multiple Endocrine Neoplasia type 1 (MEN1) have been described. Next generation sequencing (NGS) offers new possibilities for detecting mosaicism. Here we report the first study to systematically look for MEN1 mosaicism, using blood DNA, in MEN1-suspected patients but without MEN1 pathogenic variants (PV) in a heterozygous state. Methods: digital targeted NGS, including unique molecular identifiers (UMIs), was performed in routine practice and the analytic performance of this method was verified. Results: Among a cohort of 119 patients harboring from 2 to 5 MEN1 lesions, we identified 3 patients with MEN1 mosaic PVs. The allele frequencies ranged from 2.3 to 9.5%. The detection rate of MEN1 mosaicism in patients bearing at least 3 MEN1 lesions was 17% (3/18). No cases were detected in patients with 2 lesions. Conclusion: We report here 3 new cases with MEN1 mosaicism. This study examined the performance of UMI in the diagnosis of MEN1 mosaicism in routine practice and our results underline that the frequency of mosaicism is probably underestimated in patients with suspected MEN1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systematic detection of mosaicism by using digital NGS reveals three new MEN1 mosaicisms

Lagarde

Mougel

Coppins

et al. 2022

Endocrine Connections

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“…Consequently, the VAF of germline SAMD9/D9L variants is usually <30% in blood or bone marrow; however, germline DNA samples confirm VAFs of ˜50%. 10,74 While very prominent in SAMD9/D9L mutated syndromes, recent studies have identified further examples of somatic reversion in RUNX1 and GATA2 families, 75,76 as well as multiple IBMFSs, including FA, DBA and TBDs 77,78 indicating this phenomenon is more widespread than previously recognised.…”

Section: Pitfalls In Detection Of Potential Germline Variants With Tu...mentioning

confidence: 95%

Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges

2021

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Over the last decade, the field of hereditary haematological malignancy syndromes (HHMSs) has gained increasing recognition among clinicians and scientists worldwide. Germline mutations now account for almost 10% of adult and paediatric myelodysplasia/acute myeloid leukaemia (MDS/AML). As our ability to diagnose HHMSs has improved, we are now faced with the challenges of integrating these advances into routine clinical practice for patients with MDS/AML and how to optimise management and surveillance of patients and asymptomatic carriers. Discoveries of novel syndromes combined with clinical, genetic and epigenetic profiling of tumour samples, have highlighted unique patterns of disease evolution across HHMSs. Despite these advances, causative lesions are detected in less than half of familial cases and evidence-based guidelines are often lacking, suggesting there is much still to learn. Future research efforts are needed to sustain current momentum within the field, led not only by advancing genetic technology but essential collaboration between clinical and academic communities.

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“…We have limited understanding whether the remaining abnormal germline clones have the same high risk of malignant transformation. For example, in FA, revertant mosaicism in the blood may improve overall blood counts ( 47 , 140 ), but still confers a risk for leukemogenesis ( 141 ), while in the rare single cases of reversion in GATA2 deficiency ( 64 ) and RUNX1- FPD ( 66 ), hematologic malignancies have not been reported. A curious example of SGR in hematopoiesis is the case of SAMD9 and SAMD9L syndromes.…”

Section: A Diagnostic Framework To Evaluate a Suspected Germline Pred...mentioning

confidence: 99%

Lessons From Pediatric MDS: Approaches to Germline Predisposition to Hematologic Malignancies

Avagyan

Shimamura

2022

Front. Oncol.

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Pediatric myelodysplastic syndromes (MDS) often raise concern for an underlying germline predisposition to hematologic malignancies, referred to as germline predisposition herein. With the availability of genetic testing, it is now clear that syndromic features may be lacking in patients with germline predisposition. Many genetic lesions underlying germline predisposition may also be mutated somatically in de novo MDS and leukemias, making it critical to distinguish their germline origin. The verification of a suspected germline predisposition informs therapeutic considerations, guides monitoring pre- and post-treatment, and allows for family counseling. Presentation of MDS due to germline predisposition is not limited to children and spans a wide age range. In fact, the risk of MDS may increase with age in many germline predisposition conditions and can present in adults who lack classical stigmata in their childhood. Furthermore, germline predisposition associated with DDX41 mutations presents with older adult-onset MDS. Although a higher proportion of pediatric patients with MDS will have a germline predisposition, the greater number of MDS diagnoses in adult patients may result in a larger overall number of those with an underlying germline predisposition. In this review, we present a framework for the evaluation of germline predisposition to MDS across all ages. We discuss characteristics of personal and family history, clinical exam and laboratory findings, and integration of genetic sequencing results to assist in the diagnostic evaluation. We address the implications of a diagnosis of germline predisposition for the individual, for their care after MDS therapy, and for family members. Studies on MDS with germline predisposition have provided unique insights into the pathogenesis of hematologic malignancies and mechanisms of somatic genetic rescue vs. disease progression. Increasing recognition in adult patients will inform medical management and may provide potential opportunities for the prevention or interception of malignancy.

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First description of revertant mosaicism in familial platelet disorder with predisposition to acute myelogenous leukemia: correlation with the clinical phenotype

Cited by 8 publications

References 16 publications

Systematic detection of mosaicism by using digital NGS reveals three new MEN1 mosaicisms

Systematic detection of mosaicism by using digital NGS reveals three new MEN1 mosaicisms

Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges

Lessons From Pediatric MDS: Approaches to Germline Predisposition to Hematologic Malignancies

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