[Analysis of clinical phenotype and genetic variant in a case of familial hemophagocytic lymphohistiocytosis type Ⅲ].

Objective: To explore the genetic basis for a newborn with familial hemophagocytic lymphohistiocytosis type 3 (FHL3).

Methods: Clinical and laboratory data of the newborn and his family members were reviewed. Whole exome sequencing (including and flanking intronic regions) was carried out. Candidate variants were verified by Sanger sequencing. Wild type and mutant minigene vectors containing exon 23, intron 23 and exon 24 of the UNC13D gene were constructed and transfected into HEK293T cells by lipofectamine reagent. Reverse transcription PCR was carried out to verify the splicing of the minigenes.

Results: Pedigree analysis and clinical examinations indicated that the child has autosomal recessive FHL3. DNA sequencing revealed that he has harbored c.118-308 (IVS1) C>T and c.2298+1 (IVS23) G>A variants of the UNC13D gene, which were respectively inherited from his father and mother, which constituted compound heterozygosity and were both predicted to be pathogenic. Minigene experiment confirmed that the c.2298+1(IVS23) G>A variant has resulted skipping of exon 23 (-207nt) resulting in a truncated protein.

Conclusion: The c.118-308(IVS1) C>T and c.2298+1(IVS23) G>A compound heterozygous variants of the UNC13D gene probably underlay the FHL3 in this child, which has resulted in low expression as well as abnormal splicing of UNC13D mRNA.