Genetic Modifiers of Neurofibromatosis Type 1-Associated Café-au-Lait Macule Count Identified Using Multi-platform Analysis

摘要: 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 hypothesized to derive part from genetic modifiers unlinked the locus. In this study, we that normal variation germline gene expression confers risk for certain phenotypes a set 79 individuals with NF1, examined association between lymphoblastoid cell lines NF1-associated sequenced select genes significant phenotype/expression correlations. discovery cohort 89 self-reported European-Americans sequence variants these cafe-au-lait macule (CALM) count, tractable, tumor-like phenotype Two correlated, common SNPs (rs4660761 rs7161) DPH2 ATP6V0B were significantly associated CALM count. Analysis tiled regression also identified SNP rs4660761 as rs1800934 12 rare mismatch repair MSH6 Both rs7161 (DPH2 ATP6V0B) highly mega-analysis combined 180 European-Americans; (MSH6) was near-significant meta-analysis assuming dominant effect minor allele. predicted regulate ATP6V0B, melanosome biology. Individuals homozygous mutations can develop NF1-like phenotype, including multiple CALMs. Through multi-platform approach, influence