Table 4 Genetic Mutations Associated with HLH

From: Deep insight into cytokine storm: from pathogenesis to treatment

Disorder	Gene	Cytogenetic localization	MOI	Pathogenic pathway
Familial HLH⁴²¹
FHL-2	PRF1	10q21-22	AR	Pore formation
FHL-3	UNC13D	17q25	AR	Lymphocyte granule priming
FHL-4	STX11	6q24	AR	Lymphocyte granule fusion
FHL-5	STXBP2	19p13.2	AR	Lymphocyte granule fusion
Pigmentary disorders associated with HLH⁴²¹
GS-2	RAB27A	15q21	AR	Lymphocyte granule docking
CHS	LYST	1q42-43	AR	Lymphocyte granule trafficking
HPS2	AP3B1	5q14.1	AR	Lymphocyte granule trafficking
XLP-1 and XLP-2⁴²¹
XLP-1	SH2D1A	Xq25	XLR	Defective 2B4-mediated cytotoxicity, impaired T-cell restimulation-induced cell death, absent iNKT cells
XLP-2	XIAP	Xq25	XLR	Dysregulated NLRP3 inflammasome; increased effector cell susceptibility to cell death
Autoinflammation, enterocolitis⁴²¹	NLRC4	2p22.3	AD	Constitutively active NLRC4 inflammasome
NOCARH syndrome⁴²¹	CDC42	1p36.12	AD	Impaired actin structure formation, defective cell proliferation, migration, cytotoxicity, increased IL-1β and IL-18
EBV susceptibility disorders
X-linked immunodeficiency, magnesium defect⁴²¹	MAGT1	Xq21.1	XLR	Impaired Mg²⁺ transporter; low NKG2D, reduced cytotoxicity
Lymphoproliferative syndrome 1⁴²¹	ITK	5q33.3	AR	Defective tyrosine kinase function, impaired T-cell expansion, decreased iNKT cells
Lymphoproliferative syndrome 2⁴²¹	CD27	12p13.31	AR	Impaired T-cell proliferation/cytotoxicity against EBV⁺ B cells, decreased iNKT cells
Lymphoproliferative syndrome 3⁴²¹	CD70	19p13.3	AR	Defective T-cell expansion/cytotoxicity, decreased NKG2D, 2B4, iNKT cells
Immunodeficiency⁴²¹	CTPS1	1p34.3	AR	Impaired CTP synthesis for nucleic acid metabolism; defective cell proliferation, decreased iNKT cells
Immunodeficiency⁴²¹	RASGRP1	15q14	AR	Impaired T-cell activation, proliferation, migration, cytotoxicity, decreased iNKT cells
Hyperinflammatory Disorder
NCKAP1L-associated hyperinflammatory disorder⁵⁹¹	NCKAP1L	12q13.13-q13.2	AR	Impaired actin reorganization, early T-cell activation defects, impaired neutrophil migration
RC3H1-associated hyperinflammatory disorder⁵⁹²	RC3H1	1q25.1	AR	Chronic hepatitis, dyslipidemia, dysmorphic features, mild intellectual disability
RHOG-associated hyperinflammatory disorder⁵⁹³	RHOG	11p15.4	AR	Radiolucent bone lesions, sclerosis, cupping on distal metaphyses
Metabolic Disorders
Adenosine deaminase deficiency⁵⁹⁴	ADA	20q13.11	AR	Defective nucleic acid metabolism
Purine nucleoside phosphorylase deficiency⁵⁹⁵	PNP	14q13 .1	AR	Defective nucleic acid metabolism
Cobalamin C disease⁵⁹⁶	MMACHC	1p	AR	Defective vitamin B12 metabolism
Immune System Deficiencies
IL-2 Ra chain deficiency⁴²¹	1L2RA	10p15-14	AR	Impaired T-cell activation and regulation
Common γ chain deficiency⁵⁹⁷	IL-2RG	Xq13	XLR	Impaired T-cell activation and regulation
X-linked agammaglobulinemia⁵⁹⁸	BTK	Xq21.3-g22	XLR	Impaired B-cell maturation and proliferation
Wiskott-Aldrich syndrome⁵⁹⁹	WASP	Xp11.23-22	XLR	Cytoskeletal defects
DiGeorge syndrome⁶⁰⁰	DCGR	22q11.2	AD	Disrupted TBX1 pathway affects pharyngeal arch/pouch development; thymus, parathyroid, and cardiac defects
Hyper-lgD syndrome⁶⁰¹	MVK	12q24	AR	Defective cholesterol and lipid synthesis
Lysinuric protein intolerance⁴²¹	SLC7A7	14q11.2	AR	Impaired amino acid transport
Multiple sulfatase deficiency⁶⁰²	SUMF1	3p26	AR	Impaired sulfatase transcriptional activation
Holt-Oram syndrome	TBX5	12q24.1	AD	Defective cardiomyocyte differentiation
Heme oxygenase-1 deficiency⁶⁰³	HMOX1	22q12.3	AR	Impaired heme oxidation to biliverdin

AD Autosomal dominant, AR Autosomal recessive, CHS Chediak Higashi syndrome, CTP Cytidine triphosphate, GS-2 Griscelli syndrome type 2, HPS2 Hermansky-Pudlak syndrome type 2, MOI Mode of inheritance, NOCARH Neonatal onset of pancytopenia, autoinflammation, rash, & episodes of HLH, XLP-1 X-linked lymphoproliferative syndrome type 1, XLP-2 X-linked lymphoproliferative syndrome type 2, XLR X-linked recessive

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Table 4 Genetic Mutations Associated with HLH

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