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<p>The life-threatening coronavirus disease 2019 (COVID-19) affects about 1 in 1,000 healthy people under 50 without underlying conditions. Among patients with&#xa0;critical COVID-19 pneumonia, rare germline variants at genes controlling type I IFN immunity have been reported in up to 5% of patients. Causal etiologies in 80–85% of cases are still unknown. We analyzed two families with hypoxemic COVID-19 pneumonia for known single-gene inborn errors of immunity. In Family 1, two siblings with critical COVID-19 were homozygous for a <i>DOCK2</i> variant, c.3624+5G&gt;A. DOCK2 deficiency is a known T-cell disorder underlying severe viral diseases. The variant resulted in skipping exon 35, which was predicted to produce a frameshift truncated protein (p.L1157Ifs*12). The proband showed markedly decreased blood CD4 T-helper cell counts, impaired T lymphocyte transformation test, and increased serum IgG, IgA, and IgE levels, as documented in other DOCK2-deficient patients. In Family 2, the proband had lethal COVID-19 and HPV-2-associated multiple recalcitrant warts. She was heterozygous for a deletion in <i>GATA2</i>:c.1075_1102del28, p.W360Sfs*18. GATA2 haploinsufficiency is a known cause of severe viral diseases due to a lack of plasmacytoid dendritic cell (pDC) development. The proband had monocytopenia and a lack of circulating pDCs, as reported in other patients with GATA2 haploinsufficiency. Overall, both DOCK2 deficiency and GATA2 haploinsufficiency are associated with&#xa0;critical and often fatal COVID-19 pneumonia.</p>

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DOCK2 Deficiency and GATA2 Haploinsufficiency Can Underlie Critical Coronavirus Disease 2019 (COVID-19) Pneumonia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月28日

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  • Sajjad Biglari,
  • Leila Youssefian,
  • Mohammad Amin Tabatabaiefar,
  • Amir Hossein Saeidian,
  • Bahareh Abtahi‐Naeini,
  • Erfan Khorram,
  • Roya Sherkat,
  • Atefeh Sohanforooshan Moghaddam,
  • Fatemeh Mohaghegh,
  • Maziyar Rahimi,
  • Hamid Rahimi,
  • Sharareh Babaei,
  • Mohammad Shahrooei,
  • Nikoo Mozafari,
  • Shirin Zaresharifi,
  • Fatemeh Vahidnezhad,
  • Vida Homayouni,
  • Lam C. Tsoi,
  • Johann E. Gudjonsson,
  • Hakon Hakonarson,
  • Jean-Laurent Casanova,
  • Emmanuelle Jouanguy,
  • Vivien Béziat,
  • Qian Zhang,
  • Aurélie Cobat,
  • Hassan Vahidnezhad

摘要

The life-threatening coronavirus disease 2019 (COVID-19) affects about 1 in 1,000 healthy people under 50 without underlying conditions. Among patients with critical COVID-19 pneumonia, rare germline variants at genes controlling type I IFN immunity have been reported in up to 5% of patients. Causal etiologies in 80–85% of cases are still unknown. We analyzed two families with hypoxemic COVID-19 pneumonia for known single-gene inborn errors of immunity. In Family 1, two siblings with critical COVID-19 were homozygous for a DOCK2 variant, c.3624+5G>A. DOCK2 deficiency is a known T-cell disorder underlying severe viral diseases. The variant resulted in skipping exon 35, which was predicted to produce a frameshift truncated protein (p.L1157Ifs*12). The proband showed markedly decreased blood CD4 T-helper cell counts, impaired T lymphocyte transformation test, and increased serum IgG, IgA, and IgE levels, as documented in other DOCK2-deficient patients. In Family 2, the proband had lethal COVID-19 and HPV-2-associated multiple recalcitrant warts. She was heterozygous for a deletion in GATA2:c.1075_1102del28, p.W360Sfs*18. GATA2 haploinsufficiency is a known cause of severe viral diseases due to a lack of plasmacytoid dendritic cell (pDC) development. The proband had monocytopenia and a lack of circulating pDCs, as reported in other patients with GATA2 haploinsufficiency. Overall, both DOCK2 deficiency and GATA2 haploinsufficiency are associated with critical and often fatal COVID-19 pneumonia.