Phenotypic variability among individuals with neurofibromatosis type 1 (NF1) has long been a challenge for clinicians and an enigma for researchers. Members of the same family and even identical twins with NF1 often demonstrate variable disease expression. Many mechanisms for this variability have been proposed. We have performed an exploratory study of copy number variants (CNVs) as a possible source of phenotypic variability in NF1. We enrolled 11 pairs of monozygotic (MZ) twins with NF1 and their parents, catalogued their clinical characteristics, and utilized a single nucleotide polymorphism (SNP) microarray to identify CNVs in blood and saliva. The 11 twin pairs showed high concordance for presence and number of café-au-lait spots, cutaneous neurofibromas, IQ, and ADHD. They were more likely to be discordant for optic pathway glioma, plexiform neurofibromas, skeletal manifestations, and malignancy. Microarray analysis identified a total of 81 CNVs meeting our conservative criteria, 37 of which overlap known genes. Of interest, three CNVs were previously unreported. Microarray analysis failed to ascertain any CNV differences within twin pairs, between twins and parents, or between tissues in any one individual. Results of this small pilot study did not demonstrate any de novo CNV events in our MZ twin pairs, nor were de novo CNVs overrepresented in these individuals with NF1. A much larger sample size would be needed to form any conclusions about the role of CNVs in NF1 variable expressivity. Alternative explanations for discordant phenotypes include epigenetic changes, smaller genetic alterations, or environmental factors. © 2016 Wiley Periodicals, Inc.
Keywords: NF1; copy number variants; microarray; neurofibromatosis type 1; twins; variable expression.
© 2016 Wiley Periodicals, Inc.