Analysis of copy number variants in 11 pairs of monozygotic twins with neurofibromatosis type 1

Abstract

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.

Examination of the genetic factors underlying the cognitive variability associated with neurofibromatosis type 1

“…Family studies confirmed this phenotypic variability for somatic characteristics such as café-au-lait spots, optic pathway glioma, and various types of neurofibromas by showing low heritability among first and second degree affected family members 10,11 and even monozygotic (MZ) twins. 12,13 These findings suggest that a noninherited mechanism drives the etiology of somatic disease characteristics. Indeed, genetic and molecular studies reveal somatic second-hit variants in the unaffected NF1 allele (leading to loss of heterozygosity [LOH]) in many NF1related lesions.…”

Role, function and challenges of multidisciplinary centres for rare diseases exemplified for neurofibromatosis type 1 syndrome

“…Rare diseases are increasingly recognized as the orphans of medicine and have lately received special attention in Western societies. NF1 syndrome is a perfect example of the multidimensional aspects from birth to late adulthood due to the complexity of many possibly affected systems, the very individual disease burden even in genetically identical twins [10][11][12][13] and within families, and finally the limited knowledge of the disease specificities by general practitioners and paediatricians. Specialists in private practices or in hospitals almost always only see 'their' part of the disease according to their specialization, but not the whole picture.…”

Sporadic and Familial Variants in NF1: An Explanation of the Wide Variability in Neurocognitive Phenotype?

“…Copy number variants research (CNVs) also failed to understand phenotypic variability (74). In their study, the authors analyze CNVs in 11 pairs of monozygotic twins with several phenotypic discordances and concordances to identify genetic factors potentially affecting disease manifestation but found no differences in CNVs that could justify discordant NF1 characteristics (74).…”