Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by the inability to properly terminate an immune response. Familial HLH (FHLH) and related immune dysregulation syndromes are associated with mutations in the genes PRF1, UNC13D, STX11, STXBP2, LYST, AP3B1, and RAB27A, all of which are required for the assembly, exocytosis, and function of cytotoxic granules within CD8+ T cells and natural killer (NK) cells. Loss-of-function mutations in these genes render the cytotoxicity pathway ineffective, thereby failing to eradicate immune stimuli, such as infectious pathogens or malignant cells. The resulting persistent immune system stimulation drives hypercytokinemia, ultimately leading to severe tissue inflammation and end-organ damage. Traditionally, a diagnosis of FHLH requires the identification of biallelic loss-of-function mutations in one of these degranulation pathway genes. However, this narrow definition fails to encompass patients with other genetic mechanisms underlying degranulation pathway dysfunction. In particular, mounting clinical evidence supports a potential digenic mode of inheritance of FHLH in which single loss-of-function mutations in two different degranulation pathway genes cooperate to impair pathway activity. Here, we review the functions of the FHLH-associated genes within the degranulation pathway and summarize clinical evidence supporting a model in which cumulative defects along this mechanistic pathway may underlie HLH.

Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis

“…Variation in HLH genes causes congenital HLH in a recessive fashion, but it has also been suggested variants in different HLH genes could synergize to cause pathology in a digenic or oligogenic fashion. 9 We examined the set of variants that were observed in these combinations (Table 1, Supplementary Data 4) and observed that most combinations involved LYST in both cases and controls. However combinations involving LYST occurred significantly more commonly in sJIA (11/481, 2.2%) than in controls (24/2924, 0.8%; p = 0.007; OR 2.8 [1.2,6.0]).…”

“…This is consistent with the hypothesis that variants in LYST , which is involved in granule biosynthesis and generally leads to milder cytolytic defects, may interact with heterozygous variants in terminal granule processing genes and produce pathology. 9…”

Soluble interleukin-2 receptor in pediatric patients investigated for hemophagocytic lymphohistiocytosis: A single-center, 10-year-long experience

“…This may partly be due to the unavailability of genetic testing in all patients but one. Notably, no sharp demarcation exists between primary and secondary HLH, since primary HLH is often initiated by an infection or other trigger [5] and secondary HLH is often associated with a genetic predisposition [6].…”

Intravenous anakinra for the treatment of haemophagocytic lymphohistiocytosis/macrophage activation syndrome: A systematic review

“…Cytokines including interleukin (IL)‐1, IL‐6, tumour necrosis factor, and IL‐18 perpetuate systemic hyperinflammation, resulting in tissue damage, multi‐organ failure and death 1–3 . Classically, familial HLH presents in infancy with subtypes defined by specific germline variants driving immune dysfunction 4 . Secondary HLH (sHLH), also referred to as macrophage activation syndrome (MAS) in the context of rheumatological disease, is often sporadic presenting at any age, usually associated with an immunological trigger such as a systemic infection, underlying rheumatological/autoimmune disease or malignancy.…”

“…[1][2][3] Classically, familial HLH presents in infancy with subtypes defined by specific germline variants driving immune dysfunction. 4 Secondary HLH (sHLH), also referred to as macrophage activation syndrome (MAS) in the context of rheumatological disease, is often sporadic presenting at any age, usually associated with an immunological trigger such as a systemic infection, underlying rheumatological/autoimmune disease or malignancy. Clinical recognition of sHLH/MAS can be challenging, with no single pathognomonic feature and a wide spectrum of severity.…”