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Chronic myeloproliferative neoplasms

Germline duplication of ATG2B and GSKIP genes is not required for the familial myeloid malignancy syndrome associated with the duplication of chromosome 14q32

Leukemia volume 32, pages 2720–2723 (2018)Cite this article

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We read with interest the recent Perspective by Tawana and colleagues [1] discussing the advantages and disadvantages of upfront genetic testing for inherited susceptibility to myeloid neoplasms for all patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). At least 10% of patients with myeloid neoplasms are believed to have a genetic predisposition to MDS/AML [1]. One additional consideration for implementing universal genetic testing for myeloid malignancies is the still incomplete understanding of genotype–phenotype correlations for the more recently described and emerging syndromes. Recently, Saliba et al. [2] identified a novel type of myeloid neoplasm predisposition in four large West Indian families, where a germline tandem duplication of a 700 kilobase (kb) region on chromosome 14q32 conferred a highly penetrant form of a myeloid neoplasm inherited in an autosomal dominant manner. The duplicated region encompassed five protein-coding genes, TCL1A, GSKIP, ATG2B, BDKRB1, and BDKRB2. Extensive correlative studies concluded that malignant predisposition in these families was due to a germline duplication of the GSKIP and ATG2B genes and not the other genes in the duplicated region. Based on these findings, the recommended testing for familial myeloid neoplasms has been expanded to include duplications of the GSKIP and ATG2B genes [1]. Here we report a North American family with an autosomal dominant predisposition to myeloid neoplasms and a duplication of chromosome 14q32 that does not involve the GSKIP and ATG2B genes, suggesting that duplication of GSKIP and ATG2B may not be required for this autosomal dominant myeloid neoplasm predisposition syndrome.

To characterize the duplicated region more precisely, we used whole genome sequencing (WGS) in combination with polymerase chain reaction (PCR) amplification and Sanger sequencing to map the breakpoints of the rearrangement (Fig. 1b). The 1.8 Mb tandem duplication included 29 protein-coding genes and had a 56 kb region in common with the duplication reported by Saliba et al. The shared region included TCL1A, a portion of a noncoding transcript BX247990, and three regions enriched for the H3K27 histone acetylation marks (Fig. 1c). GSKIP, ATG2B, BDKRB1, and BDKRB2 genes were not duplicated (Fig. 1c). Another family in Australia with similar autosomal dominant myeloid malignancy predisposition was also found to have a duplication of chromosome 14q32 that did not include GSKIP and ATG2B [3] (Fig. 1c).

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Fig. 1

References

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Acknowledgements

We are grateful to Dr. Martin P. Carroll for establishing the Penn IRB-approved hematologic malignancies patient registry and repository, and to Dr. Monica Bessler for establishing the Penn/CHOP IRB-approved bone marrow failure patient registry and repository. We thank the proband and his sister for participation in these respective registries. We thank Dr. Peter Klein for helpful discussions. This work was supported by the NHLBI K08 HL132101 and the AA&MDS International Foundation grant to DB.

Author contributions

DB and EH designed the study and performed clinical record review, DB performed genomic analyses using WES, SNP-A, and WGS analyses, NS performed Sanger sequencing, JM and DL performed targeted somatic mutation analysis and provided invaluable banked patient samples, SC and TO contributed hematopoiesis expertise, DB, NS, JM, DL, TO, SC, and EH analyzed and interpreted the data, DB wrote the manuscript. All authors revised and approved the manuscript.

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Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Daria V. Babushok & Elizabeth O. Hexner

  2. Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Daria V. Babushok, Natasha L. Stanley & Timothy S. Olson

  3. Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Jennifer J. D. Morrissette & David B. Lieberman

  4. Blood and Marrow Transplant Program, Division of Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA

    Timothy S. Olson

  5. Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Stella T. Chou

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Correspondence to Daria V. Babushok.

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Babushok, D.V., Stanley, N.L., Morrissette, J.J.D. et al. Germline duplication of ATG2B and GSKIP genes is not required for the familial myeloid malignancy syndrome associated with the duplication of chromosome 14q32. Leukemia 32, 2720–2723 (2018). https://doi.org/10.1038/s41375-018-0231-9

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