Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis.
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 <6 months) compared to patients carrying 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.
Horne
AnnaCarin
A
Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Ramme
Kim Göransdotter
KG
Rudd
Eva
E
Zheng
Chengyun
C
Wali
Yasser
Y
al-Lamki
Zakia
Z
Gürgey
Aytemiz
A
Yalman
Nevin
N
Nordenskjöld
Magnus
M
Henter
Jan-Inge
JI
D017668:Age of Onset; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016015:Logistic Models; D051359:Lymphohistiocytosis, Hemophagocytic / Q000134:cerebrospinal fluid / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D016017:Odds Ratio; D009850:Oman / Q000208:ethnology; D054353:Perforin; D010641:Phenotype; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics*; D050765:Qa-SNARE Proteins / Q000235:genetics*; D018570:Risk Assessment / Q000379:methods; D013548:Sweden / Q000208:ethnology; D014421:Turkey / Q000208:ethnology
D008565:Membrane Proteins; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D050765:Qa-SNARE Proteins; C507969:UNC13D protein, human; D054353:Perforin