One of the most challenging aspects of managing the medical care of persons with NF1 is the extreme variability with which it affects individual patients. Some individuals may have mild involvement throughout their lifetime, while others can suffer with severe or even life-threatening complications, such as malignancies, brain tumors, or disfiguring bone complications. Despite extensive effort, no significant correlations have been found with specific NF1 gene mutations and severity of NF1 involvement. Although they have been postulated, no genes which modify the effects of the NF1 gene have yet been discovered, either. We propose a preliminary, exploratory study, using a cohort of 11 pairs of identical twins with NF1, as an innovative tool to begin to determine possible mechanisms causing NF1 variability and contributing to specific NF complications.

Study of twins has historically been a valuable tool in understanding genetic disorders. Identical twins with different NF1 complications (i.e. one with scoliosis and one without) are of particular interest, as they help us discern which complications are modified by non-inherited factors. Recent studies have shown that identical twins are not as genetically identical as originally thought. Although they inherited the same combination of genes from their parents, changes in DNA and genes may have occurred after conception (somatic mutation) that make the twins genetically different. We plan to study a group of 11 pairs of identical twins and triplets followed in our NF clinic. NF1 features of the twin pairs have already been documented, and interestingly, individual twin pairs differ in features such as scoliosis, plexiform neurofibromas, and MPNST, confirming that there are non-inherited causes of some NF1 complications. In this study, we plan to investigate the area of copy number variants (CNVs) in identical twins with NF1. CNVs are small duplications or deletions (missing copies) of DNA that have been recently found to be widely distributed in human DNA. Some CNVs may simply be variants that are passed down within families and do not affect health; however, others involve known genes and have been shown to be associated with disorders like autism, schizophrenia, developmental disabilities, and others. Interestingly, identical twins studied with other disorders (Parkinson disease) have been found to have significant differences in their CNVs, raising speculation that differences in CNVs may have caused differences (discordancies) in the features of the disorder in each twin. No one has yet investigated a possible role of CNVs in contributing to the risks for NF1 complications.

Hypothesis: Our hypothesis in this study is that identical twin pairs with NF1 will have within-pair differences in CNVs that may explain why they each have different NF1 complications. We additionally predict that the twins with NF1 will have greater numbers of new CNVs than people in the general population, due to the effect of the NF1 gene on the Ras pathway in causing increased cell division.

Study Design: We will obtain DNA from blood and cheek cells of 11 pairs of twins with NF1 (already followed in our clinic) as well as blood samples from parents of the twins. We will test each sample for CNVs using a special genetic chip called a "microarray," which can identify these small duplications and deletions of DNA. We will use special data analysis software to determine which CNVs are inherited from parents and which were acquired after conception. We will then screen all the CNVs found for regions of known genes or gene pathways which might have contributed to the specific NF1 complications of a twin.

Importance: This is a preliminary, exploratory study which will use novel techniques and a unique population of twins to investigate possible genes predisposing to serious NF1 complications such as scoliosis, plexiform neurofibromas, malignancy, or others. Identification of such modifying genes or pathways could improve clinical care by identifying patients at higher risk for serious complications. Additionally, new therapies could be targeted at the modifying genes identified in this study.