title: Mutational profiling in the peripheral blood leukocytes of patients with systemic mast cell activation syndrome using next-generation sequencing.
abstract: Mast cell activation syndrome (MCAS) and systemic mastocytosis (SM) are two clinical systemic mast cell activation disease variants. Few studies to date have investigated the genetic basis of MCAS. The present study had two aims. First, to investigate whether peripheral blood leukocytes from MCAS patients also harbor somatic mutations in genes implicated in SM using next-generation sequencing (NGS) technology and a relatively large MCAS cohort. We also addressed the question, whether some of the previously as somatic reported mutations are indeed germline mutations. Second, to identify germline mutations of relevance to MCAS pathogenesis. Here, mutation frequency in the present MCAS cohort was compared to that in public- and in-house databases in the case of frequent variants, and co-segregation was investigated in multiply affected families in the case of rare variants (allele frequency < 1%). MCAS diagnoses were assigned according to current criteria. Twenty five candidate genes were selected on the basis of published findings for SM. NGS was performed using a 76kbp custom designed Agilent SureSelect Target Enrichment and an Illumina Hiseq2000 2x100bp sequencing run. NGS revealed 67 germline mutations. No somatic mutations were detected. None of the germline mutations showed unequivocal association with MCAS. Failure to detect somatic mutations was probably attributable to the dilution of mutated mast cell DNA in normal leukocyte DNA. The present exploratory association findings suggest that some of the detected germline mutations may be functionally relevant and explain familial aggregation. Independent replication studies are therefore warranted.
authors.affiliation: Cologne Center for Genomics, University of Cologne, D-50931, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, D-50937, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), D-53127, Bonn, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Haenisch
authors.affiliation: Cologne Center for Genomics, University of Cologne, D-50931, Cologne, Germany.
authors.forename: Amit
authors.initials: A
authors.lastname: Kawalia
authors.affiliation: Division of Internal Medicine, Department of Gastroenterology and Diabetology, Community Hospital, D-53113, Bonn, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Menzen
authors.affiliation: Institute of Human Genetics, University Hospital of Bonn, D-53127, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Institute of Genomic Mathematics and Bioinformatics, University of Bonn, D-53127, Bonn, Germany.
authors.forename: Heide
authors.initials: H
authors.lastname: Fier
authors.affiliation: Institute of Human Genetics, University Hospital of Bonn, D-53127, Bonn, Germany. molderings@uni-bonn.de.
authors.forename: Gerhard J
authors.initials: GJ
authors.lastname: Molderings
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D015415:Biomarkers; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008415:Mastocytosis / Q000175:diagnosis / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome; D055815:Young Adult
chemical_list: D015415:Biomarkers
keywords: Germline mutation; Mast cell activation disease; Mast cell activation syndrome; Next-generation sequencing; Systemic mastocytosis