title: Genetic modifiers of neurofibromatosis type 1-associated café-au-lait macule count identified using multi-platform analysis.
abstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM) count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161) between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B) were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6) was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count.
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pemov
authors.affiliation: Genometrics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Heejong
authors.initials: H
authors.lastname: Sung
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hyland
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sloan
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Ruppert
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Baldwin
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Boland
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Bass
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Jones
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Xijun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: NIH Intramural Sequencing Center, National Human Genome Research Institute, Rockville, Maryland, United States of America.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.affiliation: Genometrics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Wilson
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Stewart
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D008297:Male; D056892:Mediator Complex / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C115726:DPH2 protein, human; C094443:G-T mismatch-binding protein; C098617:MED21 protein, human; C501486:MLH1 protein, human; D056892:Mediator Complex; D009687:Nuclear Proteins; D011506:Proteins; D025262:Vacuolar Proton-Translocating ATPases; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; C506979:ATP6V0B protein, human