Abstract | OBJECTIVE: METHODS: Whole-exome sequencing was used in 14 patients with systemic JIA and MAS and in their parents to identify protein-altering single-nucleotide polymorphisms/indels in known HLH-associated genes. To discover new candidate genes, the entire whole-exome sequencing data were filtered to identify protein-altering, rare recessive homozygous, compound heterozygous, and de novo variants with the potential to affect the cytolytic pathway. RESULTS: Heterozygous protein-altering rare variants in the known genes (LYST,MUNC13-4, and STXBP2) were found in 5 of 14 patients with systemic JIA and MAS (35.7%). This was in contrast to only 4 variants in 4 of 29 patients with systemic JIA without MAS (13.8%). Homozygosity and compound heterozygosity analysis applied to the entire whole-exome sequencing data in systemic JIA/MAS revealed 3 recessive pairs in 3 genes and compound heterozygotes in 73 genes. We also identified 20 heterozygous rare protein-altering variants that occurred in at least 2 patients. Many of the identified genes encoded proteins with a role in actin and microtubule reorganization and vesicle-mediated transport. "Cellular assembly and organization" was the top cellular function category based on Ingenuity Pathways Analysis (P < 3.10 × 10(-5) ). CONCLUSION: Whole-exome sequencing performed in patients with systemic JIA and MAS identified rare protein-altering variants in known HLH-associated genes as well as in new candidate genes.
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Authors | Kenneth M Kaufman, Bolan Linghu, Joseph D Szustakowski, Ammar Husami, Fan Yang, Kejian Zhang, Alexandra H Filipovich, Ndate Fall, John B Harley, N R Nirmala, Alexei A Grom |
Journal | Arthritis & rheumatology (Hoboken, N.J.)
(Arthritis Rheumatol)
Vol. 66
Issue 12
Pg. 3486-95
(Dec 2014)
ISSN: 2326-5205 [Electronic] United States |
PMID | 25047945
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | Copyright © 2014 by the American College of Rheumatology. |
Topics |
- Adolescent
- Arthritis, Juvenile
(complications, genetics)
- Child
- Child, Preschool
- Exome
- Female
- Genetic Predisposition to Disease
- Genotype
- Humans
- Infant
- Lymphohistiocytosis, Hemophagocytic
(genetics)
- Macrophage Activation Syndrome
(complications, genetics)
- Male
- Mutation
- Parents
- Polymorphism, Single Nucleotide
- Sequence Analysis, DNA
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