Pathogenic Gene Mutations or Variants Identified by Targeted Gene Sequencing in Adults With Hemophagocytic Lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) can be classified into primary HLH and secondary HLH. Primary HLH usually occurs in infants and children with an underlying genetic defect, and there are also teens and occasional adults with primary HLH. Most cases with secondary HLH are adult patients with secondary triggers including infections, malignancies, and autoimmune diseases. The distinction between primary HLH and secondary HLH seems to be less straightforward, as patients with secondary HLH may also have genetic defects while primary HLH can be triggered by secondary causes. In this study, using amplicon-based targeted gene sequencing (TGS), we sequenced eighteen HLH-related genes in 112 adult HLH cases, which were mostly secondary HLH. Mutations or rare variants were identified in 48 cases (42.9%). All the variants except one were missense variants, and biallelic gene mutations were identified in 3 cases in which only one case harbored homogenous missense mutation. Recurrent variants including UNC13D p.G863D and AP3B1 p.T359A are much more prevalent in our cohort than in normal East Asian population, and in silico analysis predicted pathogenicity of these variants. In conclusion, according to our study, genetic defects may also contribute to the development of adult HLH cases or secondary HLH cases.

Hermansky–Pudlak syndrome: Mutation update

“…Next‐generation sequencing of different cohorts of subjects with primary immunodeficiency or hemophagocytic lymphohistiocytosis (HLH) reported least eight AP3B1 variants (Table S4) in a heterozygous state with or without a variant in another (synergistic) gene. These findings suggest that heterozygous AP3B1 variants may contribute to an immunologic phenotype (Chi et al, 2018; Gallo et al, 2016; Gao, Zhu, Huang, & Zhou, 2015; Miao et al, 2019; Mukda et al, 2017; Tesi et al, 2015; Xu et al, 2017). These variants have not been reported in HPS subjects but were included in this report because they may cause HPS when occurring in a homozygous or compound heterozygous state.…”

“…Individuals with HPS‐2 that present to an immunologist with (severe) immunodeficiency may escape diagnosis due to emphasis on their immunodeficiency, other mild manifestations (e.g., hypopigmentation, ocular findings, and bleeding diathesis) may be overlooked, there may be unfamiliarity with HPS‐2, and costs and lack of availability of AP3B1 genetic testing may provide obstacles to diagnosis. However, the recent significant number of heterozygous AP3B1 variants identified by next‐generation sequencing in cohorts with immunodeficiency disorders (Chi et al, 2018; Gallo et al, 2016; Gao et al, 2015; Miao et al, 2019; Mukda et al, 2017; Tesi et al, 2015; Xu et al, 2017) emphasizes the importance of including AP3B1 in immunodeficiency‐related gene panels and may result in the diagnosis of additional HPS‐2 cases.…”

“…Heterozygous HPS1 , HPS4 , and DTNBP1 variants were reported in familial (Stearman et al, 2019) or sporadic (Deng et al, 2018) pulmonary fibrosis cases (Tables 3, 6, and 9). Heterozygous AP3B1 variants have been reported in cases with primary immunodeficiency (Chi et al, 2018; Gallo et al, 2016) or HLH (Gao et al, 2015; Miao et al, 2019; Mukda et al, 2017; Tesi et al, 2015; Xu et al, 2017; Table 4), and heterozygous variants in AP3D1 , HPS3 , and HPS4 were reported in cases with autism spectrum disorder or schizophrenia (Fromer et al, 2014; Iossifov et al, 2014; Takata et al, 2018).…”

“…These findings suggest that heterozygous AP3B1 variants may contribute to an immunologic phenotype (Chi et al, 2018;Gallo et al, 2016;Gao, Zhu, Huang, & Zhou, 2015;Miao et al, 2019;Mukda et al, 2017;Tesi et al, 2015;Xu et al, 2017). These variants have not been reported in HPS subjects but were included in this report because they may cause HPS when occurring in a homozygous or compound heterozygous state.…”

Identification of germline variants in adults with hemophagocytic lymphohistiocytosis

“…Finally, the comparatively young ages at the time of HLH onset have made distinguishing FHL that occurs in early adulthood from true adult-onset HLH difficult. [4][5][6] To overcome these issues, we sought to identify potential pathogenic germline variants in 17 genes implicated in FHL or other inherited immune disorders in a highly annotated cohort of patients diagnosed with HLH in adulthood. 7…”