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

Alexander Pemov, Heejong Sung, Paula L. Hyland, Jennifer L. Sloan, Sarah L. Ruppert, Andrea M. Baldwin, Joseph F. Boland, Sara E. Bass, Hyo Jung Lee, Kristine M. Jones, Xijun Zhang, Betty Barnabas, Robert Blakesley, Gerry Bouffard, Shelise Brooks, Holly Coleman, Mila Dekhtyar, Michael Gregory, Xiaobin Guan, Jyoti Gupta & 22 others Joel Han, Shiling Ho, Richelle Legaspi, Quino Maduro, Cathy Masiello, Baishali Maskeri, Jenny McDowell, Casandra Montemayor, Morgan Park, Nancy Riebow, Karen Schandler, Brian Schmidt, Christina Sison, Mal Stantripop, James Thomas, Pam Thomas, Meg Vemulapalli, Alice Young, James C. Mullikin, Brigitte C. Widemann, Alexander F. Wilson, Douglas R. Stewart

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalPLoS Genetics
Volume10
Issue number10
DOIs
StatePublished - Oct 1 2014
Externally publishedYes

Fingerprint

Neurofibromatosis 1
modifiers (genes)
phenotype
Single Nucleotide Polymorphism
Phenotype
gene
gene expression
germ cells
genes
pleiotropy
meta-analysis
Genes
analysis
tumor
repair
mutation
allele
Neurocutaneous Syndromes
genotype
Melanosomes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Pemov, A., Sung, H., Hyland, P. L., Sloan, J. L., Ruppert, S. L., Baldwin, A. M., ... Stewart, D. R. (2014). Genetic Modifiers of Neurofibromatosis Type 1-Associated Café-au-Lait Macule Count Identified Using Multi-platform Analysis. PLoS Genetics, 10(10). https://doi.org/10.1371/journal.pgen.1004575

Genetic Modifiers of Neurofibromatosis Type 1-Associated Café-au-Lait Macule Count Identified Using Multi-platform Analysis. / Pemov, Alexander; Sung, Heejong; Hyland, Paula L.; Sloan, Jennifer L.; Ruppert, Sarah L.; Baldwin, Andrea M.; Boland, Joseph F.; Bass, Sara E.; Lee, Hyo Jung; Jones, Kristine M.; Zhang, Xijun; Barnabas, Betty; Blakesley, Robert; Bouffard, Gerry; Brooks, Shelise; Coleman, Holly; Dekhtyar, Mila; Gregory, Michael; Guan, Xiaobin; Gupta, Jyoti; Han, Joel; Ho, Shiling; Legaspi, Richelle; Maduro, Quino; Masiello, Cathy; Maskeri, Baishali; McDowell, Jenny; Montemayor, Casandra; Park, Morgan; Riebow, Nancy; Schandler, Karen; Schmidt, Brian; Sison, Christina; Stantripop, Mal; Thomas, James; Thomas, Pam; Vemulapalli, Meg; Young, Alice; Mullikin, James C.; Widemann, Brigitte C.; Wilson, Alexander F.; Stewart, Douglas R.

In: PLoS Genetics, Vol. 10, No. 10, 01.10.2014.

Research output: Contribution to journalArticle

Pemov, A, Sung, H, Hyland, PL, Sloan, JL, Ruppert, SL, Baldwin, AM, Boland, JF, Bass, SE, Lee, HJ, Jones, KM, Zhang, X, Barnabas, B, Blakesley, R, Bouffard, G, Brooks, S, Coleman, H, Dekhtyar, M, Gregory, M, Guan, X, Gupta, J, Han, J, Ho, S, Legaspi, R, Maduro, Q, Masiello, C, Maskeri, B, McDowell, J, Montemayor, C, Park, M, Riebow, N, Schandler, K, Schmidt, B, Sison, C, Stantripop, M, Thomas, J, Thomas, P, Vemulapalli, M, Young, A, Mullikin, JC, Widemann, BC, Wilson, AF & Stewart, DR 2014, 'Genetic Modifiers of Neurofibromatosis Type 1-Associated Café-au-Lait Macule Count Identified Using Multi-platform Analysis', PLoS Genetics, vol. 10, no. 10. https://doi.org/10.1371/journal.pgen.1004575
Pemov, Alexander ; Sung, Heejong ; Hyland, Paula L. ; Sloan, Jennifer L. ; Ruppert, Sarah L. ; Baldwin, Andrea M. ; Boland, Joseph F. ; Bass, Sara E. ; Lee, Hyo Jung ; Jones, Kristine M. ; Zhang, Xijun ; Barnabas, Betty ; Blakesley, Robert ; Bouffard, Gerry ; Brooks, Shelise ; Coleman, Holly ; Dekhtyar, Mila ; Gregory, Michael ; Guan, Xiaobin ; Gupta, Jyoti ; Han, Joel ; Ho, Shiling ; Legaspi, Richelle ; Maduro, Quino ; Masiello, Cathy ; Maskeri, Baishali ; McDowell, Jenny ; Montemayor, Casandra ; Park, Morgan ; Riebow, Nancy ; Schandler, Karen ; Schmidt, Brian ; Sison, Christina ; Stantripop, Mal ; Thomas, James ; Thomas, Pam ; Vemulapalli, Meg ; Young, Alice ; Mullikin, James C. ; Widemann, Brigitte C. ; Wilson, Alexander F. ; Stewart, Douglas R. / Genetic Modifiers of Neurofibromatosis Type 1-Associated Café-au-Lait Macule Count Identified Using Multi-platform Analysis. In: PLoS Genetics. 2014 ; Vol. 10, No. 10.
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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 caf{\'e}-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.",
author = "Alexander Pemov and Heejong Sung and Hyland, {Paula L.} and Sloan, {Jennifer L.} and Ruppert, {Sarah L.} and Baldwin, {Andrea M.} and Boland, {Joseph F.} and Bass, {Sara E.} and Lee, {Hyo Jung} and Jones, {Kristine M.} and Xijun Zhang and Betty Barnabas and Robert Blakesley and Gerry Bouffard and Shelise Brooks and Holly Coleman and Mila Dekhtyar and Michael Gregory and Xiaobin Guan and Jyoti Gupta and Joel Han and Shiling Ho and Richelle Legaspi and Quino Maduro and Cathy Masiello and Baishali Maskeri and Jenny McDowell and Casandra Montemayor and Morgan Park and Nancy Riebow and Karen Schandler and Brian Schmidt and Christina Sison and Mal Stantripop and James Thomas and Pam Thomas and Meg Vemulapalli and Alice Young and Mullikin, {James C.} and Widemann, {Brigitte C.} and Wilson, {Alexander F.} and Stewart, {Douglas R.}",
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AU - Pemov, Alexander

AU - Sung, Heejong

AU - Hyland, Paula L.

AU - Sloan, Jennifer L.

AU - Ruppert, Sarah L.

AU - Baldwin, Andrea M.

AU - Boland, Joseph F.

AU - Bass, Sara E.

AU - Lee, Hyo Jung

AU - Jones, Kristine M.

AU - Zhang, Xijun

AU - Barnabas, Betty

AU - Blakesley, Robert

AU - Bouffard, Gerry

AU - Brooks, Shelise

AU - Coleman, Holly

AU - Dekhtyar, Mila

AU - Gregory, Michael

AU - Guan, Xiaobin

AU - Gupta, Jyoti

AU - Han, Joel

AU - Ho, Shiling

AU - Legaspi, Richelle

AU - Maduro, Quino

AU - Masiello, Cathy

AU - Maskeri, Baishali

AU - McDowell, Jenny

AU - Montemayor, Casandra

AU - Park, Morgan

AU - Riebow, Nancy

AU - Schandler, Karen

AU - Schmidt, Brian

AU - Sison, Christina

AU - Stantripop, Mal

AU - Thomas, James

AU - Thomas, Pam

AU - Vemulapalli, Meg

AU - Young, Alice

AU - Mullikin, James C.

AU - Widemann, Brigitte C.

AU - Wilson, Alexander F.

AU - Stewart, Douglas R.

PY - 2014/10/1

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