Variable Expression of Neurofibromatosis 1 in Monozygotic Twins

Eastern Maine Medical Center, Bangor, Maine, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 03/2011; 155A(3):478-85. DOI: 10.1002/ajmg.a.33851
Source: PubMed


Neurofibromatosis 1 (NF1) is a common autosomal dominant disorder with high penetrance but extreme variability of expression. Monozygotic (MZ) twins with NF1 who have phenotypic discordances are a useful tool in evaluating which traits are influenced by non-hereditary influences such as second hit somatic events, environmental agents, epigenetic modification, or post-zygotic mutations. We evaluated nine sets of MZ twins and one set of MZ triplets, ages 4-18 years, for NF1 features and calculated probandwise concordance (P(C)) for each feature. MZ twins were highly concordant in numbers of café-au-lait spots (P(C) = 0.89) and cutaneous neurofibromas. IQ scores were within 10 points for all twin pairs tested, and similar patterns of learning disabilities and speech disorders were observed. Twin pairs showed significant discordance for tumors, particularly plexiform neurofibromas (P(C) = 0.40) and malignant peripheral nerves sheath tumors (MPNST), as expected if post-natal second-hit events were contributing to these features. One set of twins was concordant for multiple, large paraspinal neurofibromas, suggesting that there may be more hereditary factors involved in production of paraspinal neurofibromas. Four sets were concordant for pectus deformities of the chest (P(C) = 0.80). Three sets of twins were discordant for scoliosis (P(C) = 0.40); an additional set was concordant for scoliosis but differed in presence of dystrophic features and need for surgery. Our data suggest there are additional non-hereditary factors modifying the NF1 phenotype and causing discordancies between MZ twins. Future studies may focus on differences in epigenetic changes or somatic mosaicism which have been documented for other disease genes in MZ twins.

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Available from: Lisa J Martin, Sep 18, 2014
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    • "Various degrees and forms of intellectual and social impairment are common in those with NF, affecting up to fifty percent of patients(Ferner, 2007;Ferner, 2010;Ferner et al., 2007;Hersh and American Academy of Pediatrics Committee on Genetics, 2008;Lopes Ferraz Filho et al., 2008;Committee on Genetics, 1995;NF1 Cognitive Disorders Task Force., 1997;Lu- Emerson and Plotkin, 2009a;Huson et al., 1988;Rieley et al., 2011). Specific abnormalities that have been noted include mental retardation , learning disabilities, and speech disorders(Arun and Gutmann, 2004;Lu-Emerson and Plotkin, 2009a;Rieley et al., 2011;North et al., 1997). "

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    ABSTRACT: NF1 is a highly variable and unpredictable disease. Symptom-specific genetic modifiers have been implicated as important determinants of disease development and progression. The identification of genes that affect NF1 outcome continues to be an important research goal, in part because improving the predictability of NF1 might allow stratification of patients for clinical trials as well as reducing patient anxiety. Additionally, knowing the identity of modifier genes might reveal mechanisms responsible for NF1 symptoms and identify novel therapeutic targets. The fruit fly, Drosophila melanogaster, has been used as a genetic model for over a century, and the functions of many evolutionarily conserved genes were first defined in this species. The Drosophila genome includes a single highly conserved dNF1 gene, and loss-of-function mutants have several phenotypes, including an overall growth deficiency and learning/memory defects, both of which resemble human NF1 symptoms. In this chapter, we review what has been learned in 15 years of Drosophila NF1 research, how recent work has identified at least one promising new therapeutic target, and how other knowledge obtained in Drosophila might be relevant to those interested in human NF1.
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    ABSTRACT: Although neurofibromatosis 1 (NF1) is a common Mendelian condition with an autosomal dominant pattern of inheritance, its expression is highly variable and unpredictable. Among the several causes of variable phenotypes (including intrafamilial variability) are heritable factors and environmental effects. Family studies have first suggested that the variation in expression seen in the majority of NF1 families may be caused by the influence of modifier genes unlink to the NF1 locus. Recent targeted gene strategies have allowed the identification of relevant candidates and the genomic revolution may lead to dramatic progress. © 2012 Springer-Verlag Berlin Heidelberg. All rights are reserved.
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