Characterization of PRF1, STX11 and UNC13D genotype‐phenotype correlations in familial hemophagocytic lymphohistiocytosis

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Abstract
Summary: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive lethal condition characterized by fever, cytopenia, hepatosplenomegaly and hemophagocytosis. The hallmark of FHL is defect apoptosis triggering and lymphocyte cellular cytotoxicity. Thus far three disease‐causing genes (PRF1, UNC13D, STX11) have been identified. We performed a genotype‐phenotype study in a large, multi‐ethnic cohort of 76 FHL patients originating from 65 unrelated families. Biallelic mutations in PRF1, UNC13D and STX11 were demonstrated in 13/74 (18%), 6/61 (10%) and 14/70 (20%) patients, respectively. In 27/60 (45%) patients analyzed for all three genes, no molecular diagnosis was established. STX11 mutations were most common in Turkish families (7/28, 25%), whereas in Middle East families, PRF1 mutations were most frequent (6/13, 46%). No biallelic mutation was identified in most families of Nordic origin (13/14, 93%). Patients carrying PRF1 mutations had higher risk of early onset (age STX11 mutations [adjusted odds ratio 8·23 (95% confidence interval [CI] = 1·20–56·40), P = 0·032]. Moreover, patients without identified mutations had increased risk of pathological cerebrospinal fluid (CSF) at diagnosis compared to patients with STX11 mutations [adjusted odds ratio 26·37 (CI = 1·90–366·82), P = 0·015]. These results indicate that the disease‐causing mutations in FHL have different phenotypes with regard to ethnic origin, age at onset, and pathological CSF at diagnosis.