Mutation spectrum of genetic variants in Hemophagocytic lymphohistiocytosis

Reference: Vanessa Gadoury-Levesque, Lei Dong, Rui Su, Jianjun Chen, Kejian Zhang, Kimberly A. Risma, Rebecca A. Marsh, Miao Sun; Frequency and spectrum of disease-causing variants in 1892 patients with suspected genetic HLH disorders. Blood Adv 2020; 4 (12): 2578–2594.

Journal: Blood Advances


  1. 1892 samples were retrospectively analysed, 197 samples had pathogenic or likely pathogenic variants in homozygous or compound heterozygous forms in 15 HLH related genes viz. PRF1, UNC13D, STX11, STXBP2, ITK, CD27, SH2D1A, XIAP, MAGT1, LYST, RAB27A, AP3B1, BLOC1S6, SLC7A7, and GATA2.
  2. Around 26% patients had mutation in Perforin gene, STXBP2, UNC13D and RAB27A were commonest genes with degranulation defect
  3. Diagnostic rates were highest in children less than 1 year of age and patients with Familial HLH 2-5 were referred and diagnosed early as compared to other genes
  4. Missense variants were common in PRF and STXBP2 genes and splice-site variants were common in UNC13D & STXBP2
  5. Significant proportion of remaining patients had secondary HLH due to malignancy, autoimmunity or infection and currently whole genome sequencing may not be cost effective for all cases with HLH

Bottom line: As point mutations, small deletions and insertions are the commonest changes in HLH related genes, NGS based approach will capture them with high accuracy though better algorithms need to be used to reliably identify large deletions, duplications and insertion