Identification of a novel nonsense mutation in the UNC13D gene from a patient with hemophagocytic lymphohistiocytosis: a case report

Background: Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous and potentially fatal disease that presents symptoms of persistent fever, splenomegaly and cytopenia. Primary HLH is identified as an autosomal recessive disorder with causative genes including HPLH1, PRF1, UNC13D, STX11 and STXBP2. Case presentation: Here, we reported an 8-month-old female patient with compound heterozygosity in the UNC13D gene. The patient, who presented typical symptoms, was diagnosed with HLH based on HLH-2004 guidelines. High-throughput amplicon sequencing for the full-length exon, including a 5 bp padding region and 6 HLH-related genes, was performed to identify the pathogenic mutations in this patient. In all, 9 heterozygous variations were detected, namely, 7 nonpathogenic SNPs, one nonsense mutation (NM_199242.2:c.2206C > T, p.Gln736X), and one splicing mutation (NM_199242.2:c.2709 + 1G > A). These two mutations were considered pathogenic according to previous studies and functional prediction. A two-generation pedigree analysis based on Sanger sequencing was performed to confirm the result. Conclusion: Compound heterozygosity in the UNC13D gene was identified in trans and considered a causative mutation in a female patient with HLH. The nonsense mutation (NM_199242.2:c.2206C > T, p.Gln736X) was novel in cases of HLH. Our data expand the spectrum of HLH-related mutations in China and demonstrate the potential of high-throughput amplicon sequencing in the diagnosis of HLH.