clinical and genetic analysis of nine suspected familial haemophagocytic lymphohistiocytosis patients for munc13-4 deficiency and introducing four novel mutations in unc13d

Familial haemophagocytic lymphohistiocytosis (fhl) is a rare disorder of immune dysregulation. fhl inherited in an autosomal recessive pattern is classified into five subtypes based on underlying genetic defects. mutations in four genes including prf1, unc13d, stx11 and stxbp2 are responsible for fhl2 to fhl5 respectively. the cause of fhl1 is associated with mutations in an unknown gene located at 9q21.3-22. this study aims to report the clinical features and genetic results of nine iranian patients suffering from - haemophagocytic lymphohistiocytosis. nine patients (five males and four females) suspected to fhl whose genetic evaluation of prf1 and stx11 revealed no mutations, were entered the study to investigate unc13d mutations. primers were designed to amplify all coding regions and exon-intron boundaries of the gene. pcr products were then sequenced and analyzed by sequence analysis tools including blast. the most frequent clinical manifestations observed in the patients were fever and hepatosplenomegaly. in this study, five mutations were detected in unc13d including four novel mutations (c.1434_1446delacccatggtgcaginstggtgct, c.1933c>t, c.1389+1g>c and c.2091+1g>a) besides to a previously reported deletion (c.627delt). the pathogenicity of the missense mutation was assessed using online prediction tools including sift and polyphen2. the study results may provide valuable information for genetic counseling especially for those who have a history of immunodeficiency diseases in their family and can be used for prenatal diagnosis.