Monozygotic twins discordant for neurofibromatosis type 1 due to a postzygotic NF1 gene mutation

Abstract

ABSTRACT:The analysis of monozygotic twins (MZ) concordant for neurofibromatosis type 1 (NF1) has indicated that genetic factors exert a major influence on the clinical variability (e.g. the number of café-au-lait spots and/or neurofibromas) evident in this disease. Here, we report on a pair of monozygotic, dichorionic twins who are phenotypically discordant with respect to NF1. Whereas DNA sequence analysis indicated somatic mosaicism for the NF1 nonsense mutation, c.4108C>T (p.Q1370X), in the affected twin II/1, this lesion was apparently absent in his unaffected brother. The observation of heterozygosity for flanking SNP and microsatellite markers rendered it most unlikely that the observed mosaicism with normal cells was due to mutation reversion brought about either by gene conversion or mitotic recombination. Instead, we conclude that the twinning event, which would have taken place within three days post-fertilization, must have preceded the c.4108C>T mutation which is therefore predicted to have occurred during the blastocyst stage, leading to somatic mosaicism with normal cells lacking the mutation. This is the first reported case of monozygotic twins discordant for NF1 in whom mosaicism for a postzygotic NF1 gene mutation has been observed in the affected but not the unaffected twin. ©2011 Wiley-Liss, Inc.

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

“…Miesfeldt et al 1998; Munhoz et al 2008; McDade et al 2012), others are quite discordant (Matsuo et al 2000; Amann et al 2001; Martin et al 2003; Holmgren et al 2004; Lachmann et al 2004; Czlonkowska et al 2009; Biegstraaten et al 2011; Fencl et al 2012; Iatropoulos et al 2012), suggesting that the environment can often play an important role in determining both the penetrance and expressivity of pathological mutations. [It should be borne in mind that there are various alternative genetic explanations for discordant phenotypes in monozygotic twins, including de novo post-zygotic mutation (Kentsis et al 2009; Vogt et al 2011), compensatory mutations (Mankad et al 2006) and somatic copy number variation (Bruder et al 2008) that obviate the need for a major contribution from the environment, as well as acquired epigenetic differences (Galetzka et al 2012; Bennett et al 2008)].…”

Neurofibromatosis type 1: from genotype to phenotype

“…Few MZ twins with markedly different NF1 features have been described,15 but the causative mutations were not always identified. In a recent study of a pair of MZ twins, only one of whom had a NF1 phenotype, a postzygotic NF1 gene mutation (leading to somatic mosaicism for the NF1 mutation) was exclusively identified in the affected twin 16. Plexiform neurofibromas tend to be less concordant than other features in twins with NF1.…”

Somatic Activation of AKT3 Causes Hemispheric Developmental Brain Malformations

“…Other neurodevelopmental disorders occasionally result from somatic mutations, including DCX (Gleeson et al, 2000) and NF1 (Messiaen et al, 2011; Vogt et al, 2011), but these have generally not been mutations limited to brain. In addition, some tubers from individuals with TSC, who carry germline mutations in TSC1 or TSC2, have been demonstrated to have somatic “second hits’ in the TSC2 gene (Qin et al, 2010).…”