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

TY - JOUR

T1 - Monozygotic twins discordant for neurofibromatosis type 1 due to a postzygotic NF1 gene mutation.

AU - Vogt, Julia

AU - Kohlhase, Jürgen

AU - Morlot, Susanne

AU - Kluwe, Lan

AU - Mautner, Viktor Felix

AU - Cooper, David N

AU - Kehrer-Sawatzki, Hildegard

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

KW - Humans

KW - Male

KW - Child, Preschool

KW - Mutation

KW - Phenotype

KW - Pedigree

KW - Polymorphism, Single Nucleotide

KW - Sequence Analysis, DNA

KW - Heterozygote

KW - Neurofibromin 1/genetics

KW - Mosaicism

KW - Neurofibromatosis 1/genetics

KW - Cafe-au-Lait Spots/genetics

KW - Twins, Monozygotic/genetics

KW - Zygote

KW - Humans

KW - Male

KW - Child, Preschool

KW - Mutation

KW - Phenotype

KW - Pedigree

KW - Polymorphism, Single Nucleotide

KW - Sequence Analysis, DNA

KW - Heterozygote

KW - Neurofibromin 1/genetics

KW - Mosaicism

KW - Neurofibromatosis 1/genetics

KW - Cafe-au-Lait Spots/genetics

KW - Twins, Monozygotic/genetics

KW - Zygote

M3 - SCORING: Journal article

VL - 32

SP - 2134

EP - 2147

JO - HUM MUTAT

JF - HUM MUTAT

SN - 1059-7794

IS - 6

M1 - 6

ER -