Novel Frameshift Autosomal Recessive Loss-of-Function Mutation in SMARCD2 Encoding a Chromatin Remodeling Factor Mediates Granulopoiesis



Recently, a new form of congenital neutropenia that is caused by germline biallelic loss-of-function mutations in the SMARCD2 gene was described in four patients. Given the rarity of the condition, the clinical spectrum of the disease has remained elusive. We here report a new patient with a novel frameshift mutation and compare our patient with the previously reported SMARCD2-mutant patients, aiming to provide a more comprehensive understanding of the natural course of the disease.


Clinical and laboratory findings of all reported patients were reviewed. Next-generation sequencing was performed to identify the causative genetic defect. Data on the hematopoietic stem cell transplantation including stem cell sources, conditioning regimen, engraftment, graft-versus-host disease, and infections were also collected.


An 11-year-old female patient had a variety of infections including sepsis, deep tissue abscesses, otitis, pneumonia, gingivitis, and diarrhea since infancy. A novel homozygous mutation in SMARCD2 (c.93delG, p.Ala32Argfs*80) was detected. Bone marrow examination showed hypocellularity and decreased neutrophils with diminished granules and myeloid dysplasia, but no blast excess as in previously reported patients. The neutropenia was non-responsive even to higher doses of granulocyte colony-stimulating factor (G-CSF); therefore, the patient was transplanted at 10 years of age from a HLA-A allele–mismatched unrelated donor using a reduced toxicity conditioning regimen and recovered successfully. Compared with the previous four cases, our patient showed longer survival before transplantation without blastic transformation.


Distinctive myeloid features and long-term follow-up including therapy options are presented for the newly described case of SMARCD2 deficiency. This disorder is apparent at infancy and requires early transplantation due to the unrelenting disease course despite conventional therapy.

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  1. 1.

    Boztug K, Klein C. Genetics and pathophysiology of severe congenital neutropenia syndromes unrelated to neutrophil elastase. Hematol Oncol Clin North Am. 2013;27(1):43–60 vii.

    Article  Google Scholar 

  2. 2.

    Kostmann R. Infantile genetic agranulocytosis; agranulocytosis infantilis hereditaria. Acta Paediatr Suppl. 1956;45(Suppl 105):1–78.

    CAS  PubMed  Google Scholar 

  3. 3.

    Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schaffer AA, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet. 2007;39(1):86–92.

    CAS  Article  Google Scholar 

  4. 4.

    Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40(1):24–64.

    Article  Google Scholar 

  5. 5.

    Boztug K, Jarvinen PM, Salzer E, Racek T, Monch S, Garncarz W, et al. JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia. Nat Genet. 2014;46(9):1021–7.

    CAS  Article  Google Scholar 

  6. 6.

    Boztug K, Appaswamy G, Ashikov A, Schaffer AA, Salzer U, Diestelhorst J, et al. A syndrome with congenital neutropenia and mutations in G6PC3. N Engl J Med. 2009;360(1):32–43.

    CAS  Article  Google Scholar 

  7. 7.

    Kiykim A, Garncarz W, Karakoc-Aydiner E, Ozen A, Kiykim E, Yesil G, et al. Novel CLPB mutation in a patient with 3-methylglutaconic aciduria causing severe neurological involvement and congenital neutropenia. Clin Immunol. 2016;165:1–3.

    CAS  Article  Google Scholar 

  8. 8.

    Kiykim A, Baris S, Karakoc-Aydiner E, Ozen AO, Ogulur I, Bozkurt S, et al. G6PC3 deficiency: primary immune deficiency beyond just neutropenia. J Pediatr Hematol Oncol. 2015;37(8):616–22.

    CAS  Article  Google Scholar 

  9. 9.

    Witzel M, Petersheim D, Fan Y, Bahrami E, Racek T, Rohlfs M, et al. Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes. Nat Genet. 2017;49(5):742–52.

    CAS  Article  Google Scholar 

  10. 10.

    Priam P, Krasteva V, Rousseau P, D’Angelo G, Gaboury L, Sauvageau G, et al. SMARCD2 subunit of SWI/SNF chromatin-remodeling complexes mediates granulopoiesis through a CEBPvarepsilon dependent mechanism. Nat Genet. 2017;49(5):753–64.

    CAS  Article  Google Scholar 

  11. 11.

    Lekstrom-Himes JA, Dorman SE, Kopar P, Holland SM, Gallin JI. Neutrophil-specific granule deficiency results from a novel mutation with loss of function of the transcription factor CCAAT/enhancer binding protein epsilon. J Exp Med. 1999;189(11):1847–52.

    CAS  Article  Google Scholar 

  12. 12.

    Lawrence SM, Corriden R, Nizet V. The ontogeny of a neutrophil: mechanisms of granulopoiesis and homeostasis. Microbiol Mol Biol Rev. 2018;82(1).

  13. 13.

    Kiykim A, Ogulur I, Dursun E, Charbonnier LM, Nain E, Cekic S, et al. Abatacept as a long-term targeted therapy for LRBA deficiency. J Allergy Clin Immunol Pract. 2019;7(8):2790–800 e15.

    Article  Google Scholar 

  14. 14.

    Erman B, Bilic I, Hirschmugl T, Salzer E, Boztug H, Sanal O, et al. Investigation of genetic defects in severe combined immunodeficiency patients from Turkey by targeted sequencing. Scand J Immunol. 2017;85(3):227–34.

    CAS  Article  Google Scholar 

  15. 15.

    Gombart AF, Shiohara M, Kwok SH, Agematsu K, Komiyama A, Koeffler HP. Neutrophil-specific granule deficiency: homozygous recessive inheritance of a frameshift mutation in the gene encoding transcription factor CCAAT/enhancer binding protein--epsilon. Blood. 2001;97(9):2561–7.

    CAS  Article  Google Scholar 

  16. 16.

    Wada T, Akagi T, Muraoka M, Toma T, Kaji K, Agematsu K, et al. A novel in-frame deletion in the leucine zipper domain of C/EBPepsilon leads to neutrophil-specific granule deficiency. J Immunol. 2015;195(1):80–6.

    CAS  Article  Google Scholar 

  17. 17.

    Shigemura T, Yamazaki T, Shiohara M, Kobayashi N, Naganuma K, Koike K, et al. Clinical course in a patient with neutrophil-specific granule deficiency and rapid detection of neutrophil granules as a screening test. J Clin Immunol. 2014;34(7):780–3.

    Article  Google Scholar 

  18. 18.

    Leszcynska M, Patel B, Morrow M, Chamizo W, Tuite G, Berman DM, et al. Brain abscess as severe presentation of specific granule deficiency. Front Pediatr. 2020;8:117.

    Article  Google Scholar 

  19. 19.

    Michel BC, Kadoch C. A SMARCD2-containing mSWI/SNF complex is required for granulopoiesis. Nat Genet. 2017;49(5):655–7.

    CAS  Article  Google Scholar 

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This work was supported by the Scientific and Technological Research Council of Turkey to S.B. (318S202).

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Correspondence to Safa Baris.

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The genetic analysis of the patient was approved by the local ethics committee of Marmara University with the protocol code 0920130268 and written informed consents were obtained from the patient and her parents.

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The authors declare that they have no conflict of interest.

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Yucel, E., Karakus, I.S., Krolo, A. et al. Novel Frameshift Autosomal Recessive Loss-of-Function Mutation in SMARCD2 Encoding a Chromatin Remodeling Factor Mediates Granulopoiesis. J Clin Immunol 41, 59–65 (2021).

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  • SWI/SNF complex
  • neutropenia
  • specific granule deficiency
  • hematopoietic stem cell transplantation