Genetic and molecular approaches for patients with familial hemophagocytic lymphohistiocytosis: a multi-center experience from Mexico.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition that results from a severe inflammation caused by an exaggerated immune response. HLH may have a genetic cause affecting the proper function of cytotoxic immune cells or it canbe linked to other pathological settings including inborn errors of immunity, malignancies, autoinflammatory and autoimmune syndromes, metabolic diseases, or acquired immunodeficiencies. HLH due to a genetic error remains difficult to diagnose because anormal Natural Killer (NK) or cytotoxic T lymphocyte (CTL) function does not necessarily exclude a familial form of HLH affecting immune cells other than cytotoxic lymphocytes, or because patients with autoimmune or autoinflammatory syndromes can also fulfill the HLH criteria. In consequence, sensitive functional assays and assessment of the expression of proteins involved in lytic-granules exocytosis may be useful approaches for discriminating between familial forms of HLH from those where a genetic cause is not affecting cytotoxic cell function, or from acquired forms of HLH.

METHODS: By different approaches, including functional assays and biochemical studies, we were able to obtain molecular diagnostics for patients, while next-generation sequencing identified the disease-associated gene variants.

RESULTS: Here we presented a multi-center experience in approaching and diagnosing patients with familial HLH. Our study included a cohort of 31 patients that fulfill the criteria of HLH. Genetic testing, led to identified variants in PRF1, UNC13D, STX11, STXBP2, RAB27A, LYST, AP3B1 and SH2D1A, confirming most of the initial molecular diagnoses. From allfound variants, 15 were novel and not previously reported in patients with HLH nor found in homozygous condition.

DISCUSSION: Our results highlight the importance of taking into consideration molecular studies to increase the proportion of patients that obtain a molecular diagnosis, especially in countries where high-throughput genetic analyses are difficult to access or time-consuming.