Genome-wide association study of café-au-lait macule number in neurofibromatosis type 1 - PubMed

Genome-wide association study of café-au-lait macule number in neurofibromatosis type 1 - PubMed

Genome-wide association study of café-au-lait macule number in neurofibromatosis type 1

Heejong Sung 1, Paula L Hyland 2 3, Alexander Pemov 4, Jeremy A Sabourin 1, Andrea M Baldwin 5, Sara Bass 6, Kedest Teshome 6, Wen Luo 6, Frederick National Laboratory for Cancer Research; Brigitte C Widemann 5, Douglas R Stewart 4, Alexander F Wilson 1

Affiliations 

• PMID: 32869517
 
• DOI: 10.1002/mgg3.1400

Free article

Abstract

Background: Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder that arises due to pathogenic variants in tumor suppressor NF1. NF1 has variable expressivity that may be due, at least in part, from heritable elements such as modifier genes; however, few genetic modifiers have been identified to date.

Methods: In this study, we performed a genome-wide association analysis of the number of café-au-lait macules (CALM) that are considered a tumor-like trait as a clinical phenotype modifying NF1.

Results: A borderline genome-wide significant association was identified in the discovery cohort (CALM1, N = 112) between CALM number and rs12190451 (and rs3799603, r2 = 1.0; p = 7.4 × 10-8 ) in the intronic region of RPS6KA2. Although, this association was not replicated in the second cohort (CALM2, N = 59) and a meta-analysis did not show significantly associated variants in this region, a significant corroboration score (0.72) was obtained for the RPS6KA2 signal in the discovery cohort (CALM1) using Complementary Pairs Stability Selection for Genome-Wide Association Studies (ComPaSS-GWAS) analysis, suggesting that the lack of replication may be due to heterogeneity of the cohorts rather than type I error.

Conclusion: rs12190451 is located in a melanocyte-specific enhancer and may influence RPS6KA2 expression in melanocytes-warranting further functional studies.

Keywords: café-au-lait macule; complementary pairs stability selection for genome-wide association studies analysis; genetic modifiers; genome-wide association study; neurofibromatosis type 1.

© Published 2020. This article is a U.S. Government work and is in the public domain in the USA. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

Similar articles

• Genetic modifiers of neurofibromatosis type 1-associated café-au-lait macule count identified using multi-platform analysis.

  Pemov A, Sung H, Hyland PL, Sloan JL, Ruppert SL, Baldwin AM, Boland JF, Bass SE, Lee HJ, Jones KM, Zhang X; NISC Comparative Sequencing Program, Mullikin JC, Widemann BC, Wilson AF, Stewart DR.PLoS Genet. 2014 Oct 16;10(10):e1004575. doi: 10.1371/journal.pgen.1004575. eCollection 2014 Oct.PMID: 25329635 Free PMC article.
• Diagnostic value of multiple café-au-lait macules for neurofibromatosis 1 in Chinese children.

  Yao R, Wang L, Yu Y, Wang J, Shen Y.J Dermatol. 2016 May;43(5):537-42. doi: 10.1111/1346-8138.13169. Epub 2015 Oct 13.PMID: 26458495
• Café-au-lait Macules and Neurofibromatosis Type 1: A Review of the Literature.

  Bernier A, Larbrisseau A, Perreault S.Pediatr Neurol. 2016 Jul;60:24-29.e1. doi: 10.1016/j.pediatrneurol.2016.03.003. Epub 2016 Mar 19.PMID: 27212418 Review.
• Café-au-lait spots in neurofibromatosis type 1 and in healthy control individuals: hyperpigmentation of a different kind?

  De Schepper S, Boucneau J, Vander Haeghen Y, Messiaen L, Naeyaert JM, Lambert J.Arch Dermatol Res. 2006 Apr;297(10):439-49. doi: 10.1007/s00403-006-0644-6. Epub 2006 Feb 15.PMID: 16479403
• An Update on Neurofibromatosis Type 1: Not Just Café-au-Lait Spots and Freckling. Part II. Other Skin Manifestations Characteristic of NF1. NF1 and Cancer.

  Hernández-Martín A, Duat-Rodríguez A.Actas Dermosifiliogr. 2016 Jul-Aug;107(6):465-73. doi: 10.1016/j.ad.2016.01.009. Epub 2016 Mar 5.PMID: 26956402 Review. English, Spanish.