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Mutational profiling of a MonoMAC syndrome family with GATA2 deficiency

Leukemia volume 31, pages 244–245 (2017)Cite this article

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MonoMAC is an autosomal-dominant syndrome and manifests as a deficiency of monocytes, B lymphocytes and NK cells. It is often accompanied with mycobacterial, fungal and viral infections.1 This rare genetic disorder was initially described a few years ago2 and subsequent studies then revealed mutation of the transcription factor GATA2 as the cause of the syndrome.3, 4, 5, 6, 7 Although targeted sequencing or exome sequencing has been performed recently and a number of cooperating mutations has been found in several studies,3, 4, 6, 8 to our knowledge, the entire spectrum of genomic changes of this disease has not yet been characterized.

The studied family includes two disease-affected patients (father and son) and a disease-free daughter. Both father and son experienced repeated infections and were diagnosed with MDS at ages 18 and 17, respectively. They remained healthy after receiving hematopoietic stem cell transplantation from unrelated donors. Genomic DNA was extracted from the father’s malignant paraffin-embedded bone marrow before transplantation, as well as from a swab of the mouth mucosa (germline control), the son’s paraffin-embedded bone marrow before transplantation and his mouth swab, as well as the healthy daughter’s bone marrow together with her normal cells from the mouth swab. Whole-genome sequencing was performed on the above samples using Illumina HiSeq X Ten (mean >30X coverage). Exome sequencing of the son’s bone marrow sample was also performed using Illumina Hiseq4000 (mean >200X coverage) to enhance the identification of potential subclonal mutations. The sequencing reads were aligned to the standard human genome (hg19) using BWA, and mutations were called using Mutect (for single-nucleotide variants, SNVs), VarScan (for SNVs and indels), Pindel (for indels) and Delly (for structural variants). Results were filtered with dbSNP131, 1000 genome (cutoff >0.001), Esp5400 database (cutoff >0.001), and the repetitive and low complexity regions (repeats and genomic SuperDups track, UCSC Genome Browser). Inactivating germline mutations (nonsense, frameshift and splicing-site mutations) were further analyzed. All the germline variants of the GATA2 gene, including coding region, intron, UTR and upstream/downstream, were called and filtered with dbSNP131, 1000 genome, Esp5400 database and further examined using ExAC exome database (http://exac.broadinstitute.org/).

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Acknowledgements

This research is supported by the National Research Foundation Singapore under its Singapore Translational Research (STaR) Investigator Award (NMRC/STaR/0021/2014) and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC), the NMRC Centre Grant awarded to National University Cancer Institute of Singapore, the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives. This research is supported by the National Institutes of Health of the USA (R01CA026038-35), as well as by a generous donation from the Melamed family.

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Author notes

  1. L-W Ding, T Ikezoe and K-T Tan: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Science Institute of Singapore, National University of Singapore, Singapore

    L-W Ding, K-T Tan, A Mayakonda, W Chien, D-C Lin, Y-Y Jiang, H Yang, Q-Y Sun & H P Koeffler

  2. Department of Hematology, Fukushima Medical University, Fukushima, Japan

    T Ikezoe

  3. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan

    M Mori

  4. Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA

    D-C Lin, M Lill & H P Koeffler

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  1. L-W Ding
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Correspondence to Q-Y Sun.

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Ding, LW., Ikezoe, T., Tan, KT. et al. Mutational profiling of a MonoMAC syndrome family with GATA2 deficiency. Leukemia 31, 244–245 (2017). https://doi.org/10.1038/leu.2016.256

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