Variation in Gene Expression in Neurofibromatosis Type 1
We hypothesize that normal germline variation in gene expression accounts, in part, for
variation in the clinical severity and phenotype of the monogenic disorder neurofibromatosis
type 1 (NF1). The phenotype of NF1 is constituted by a variety of quantifiable features; we
term these features sub-phenotypes . Our main focus is on sub-phenotypes with published
evidence of variation in expression from an inherited component. These include our primary
sub-phenotype of spinal neurofibroma burden (quantified by MRI of spinal neurofibromas) and
the secondary sub-phenotypes of dermal neurofibroma burden, head circumference, number of
Lisch nodules, scoliosis, history of plexiform neurofibromas, and height. Other
sub-phenotypes, as collected by a routine history and physical, will also be evaluated.
According to our hypothesis, the severity of a sub-phenotype will correlate with heritable
differences in the germline expression of certain genes. As an example, consider a spectrum
of individuals affected with the primary sub-phenotype of spinal neurofibroma burden. For
most genes, there will be no relationship of expression level to the number of spinal
neurofibromas. However, some genes will have a direct (or inverse, or other) correlation of
their level of expression and the number of neurofibromas. Such genes would be considered
as candidate modifier genes. The secondary sub-phenotypes will also be analyzed in a
similar way. To limit false positives, candidate genes will then be tested for association
(using the transmission/disequilibrium test, TDT) with the appropriate sub-phenotype.
Recruitment will be focused on identifying individuals with a range of severity of the
primary sub-phenotype, spinal neurofibroma burden. We will primarily recruit post-pubertal
individuals who meet the 1988 NIH criteria for neurofibromatosis type 1 (NIH Consensus
Development Conference 1988). We will exclude those with recognized segmental or mosaic
NF1. The rate of cutaneous neurofibroma growth and number is known to vary widely; these
tumors typically appear in adolescence. For this reason we will ascertain patients after
puberty. We expect most individuals to be 18 years or older, but will also accept
post-pubertal pediatric patients (and use a hand film to demonstrate bone age). Parents
(whether affected or not) are critical when using family-based tests of association (like
the TDT) and tests of linkage and will also be recruited.
Tests of association with the TDT require trios (mother, father, proband). Multiple trios
can be derived from a single family, if there are multiple affected individuals within the
family. We set a recruitment goal of 100 trios and a ceiling of 1500 individuals (500
affected individuals, plus 1000 parents or additional sibs in about 400 families).
In the interest of improving care for people living with NF1, this protocol also seeks to
characterize, at the PI's discretion, individuals with unique or under-recognized features
of NF1 as well as individuals with NF1-like phenotypes, including those patients with a
known or suspected RAS pathway disorder.
Douglas R Stewart, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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