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

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.

Craniopharyngiomas : Radiological Differentiation of Two Types.

OBJECTIVE: To determine imaging features that may separate adamantinomatous and papillary variants of craniopharyngiomas given that tumors with adamantinomatous signature features are associated with higher recurrence rates, morbidity, and mortality. We specifically reviewed calcification on CT, T1 bright signal intensity, and cystic change on T2 weighted images for differentiating these two types. METHODS: We retrospectively reviewed the MRI and CT studies in 38 consecutive patients with pathologically proven craniopharyngiomas between January 2004 and February 2014 for the presence of calcification on CT scans, bright signal intensity on T1 weighted images, and cystic change on T2 weighted images. RESULTS: Of the 38 craniopharyngiomas, 30 were adamantinomatous type and 8 were papillary type. On CT scans, calcification was present in 25 of 38 tumors. All calcified tumors were adamantinomatous type. Twenty four of 38 tumors had bright signal intensity on T1 weighted images. Of these 24 tumors, 22 (91.7%) were adamantinomatous and 2 were papillary type. Cystic change on T2 weighted images was noted in 37 of 38 tumors; only 1 tumor with papillary type did not show cystic change. CONCLUSION: T1 bright signal intensity and calcification on CT scans uniformly favor the adamantinomatous type over papillary type of craniopharyngioma in children. However, these findings are more variable in adults where calcification and T1 bright signal intensity occur in 70.6% and 58.8% respectively of adult adamantinomatous types of craniopharyngiomas.

Visual Defects in Patients With Pituitary Adenomas: The Myth of Bitemporal Hemianopsia.

OBJECTIVE: The objective of this study was to test the hypothesis that bitemporal hemianopsia (BHA) is the most common visual field (VF) defect in patients with pituitary macroadenoma and to assess the degree of optic pathway compression necessary to produce visual defects. MATERIALS AND METHODS: We reviewed the MRI findings and medical records of 119 patients with pituitary macroadenoma who had undergone formal assessment of VFs. We then evaluated the degree of optic pathway displacement caused by the pituitary macroadenoma, as observed on MR images. The classifications of optic pathway displacement included no contact, abutment but no displacement, mild displacement (< 3 mm), and moderate displacement (≥ 3 mm). Qualitative analysis classified VFs as normal or as having defects that were monocular, bitemporal, mixed (bitemporal with additional defects), homonymous, or nonspecific. RESULTS: A total of 89 of 115 patients had an abnormal VF. Only one patient had true BHA. The most common defects were bitemporal or mixed defects (in 49 of 115 patients [42.6%]), likely because more than just the chiasm is often compressed by the pituitary macroadenoma. Classification of optic pathway displacement by the pituitary macroadenoma was as follows: 23 patients had no contact, eight had abutment but no displacement, 27 had mild displacement, and 57 had moderate displacement. In 78 of the 92 patients (84.8%) with pituitary macroadenoma that had contact with the optic pathway, contact was with the optic chiasm and the prechiasmal optic nerve. Of the 49 patients with bitemporal or mixed defects, 42 had moderate displacement of the optic pathway caused by their tumors. CONCLUSION: BHA is exceedingly uncommon in patients with pituitary macroadenoma. However, although bitemporal and mixed defects are the most common abnormal VF findings, they were found in only 42.6% of patients. Such defects rarely occur if the tumor displaces the optic pathway less than 3 mm from baseline.

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

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.

Evaluation of random forests performance for genome-wide association studies in the presence of interaction effects.

Random forests (RF) is one of a broad class of machine learning methods that are able to deal with large-scale data without model specification, which makes it an attractive method for genome-wide association studies (GWAS). The performance of RF and other association methods in the presence of interactions was evaluated using the simulated data from Genetic Analysis Workshop 16 Problem 3, with knowledge of the major causative markers, risk factors, and their interactions in the simulated traits. There was good power to detect the environmental risk factors using RF, trend tests, or regression analyses but the power to detect the effects of the causal markers was poor for all methods. The causal marker that had an interactive effect with smoking did show moderate evidence of association in the RF and regression analyses, suggesting that RF may perform well at detecting such interactions in larger, more highly powered datasets.