Abstract
Monozygotic (identical) twins have been widely used in genetic studies to determine the relative contributions of heredity and the environment in human diseases. Discordance in disease manifestation between affected monozygotic twins has been attributed to either environmental factors or different patterns of X chromosome inactivation (XCI). However, recent studies have identified genetic and epigenetic differences between monozygotic twins, thereby challenging the accepted experimental model for distinguishing the effects of nature and nurture. Here, we report the genomic and epigenomic sequences in skin fibroblasts of a discordant monozygotic twin pair with Rett syndrome, an X-linked neurodevelopmental disorder characterized by autistic features, epileptic seizures, gait ataxia and stereotypical hand movements. The twins shared the same de novo mutation in exon 4 of the MECP2 gene (G269AfsX288), which was paternal in origin and occurred during spermatogenesis. The XCI patterns in the twins did not differ in lymphocytes, skin fibroblasts, and hair cells (which originate from ectoderm as does neuronal tissue). No reproducible differences were detected between the twins in single nucleotide polymorphisms (SNPs), insertion-deletion polymorphisms (indels), or copy number variations. Differences in DNA methylation between the twins were detected in fibroblasts in the upstream regions of genes involved in brain function and skeletal tissues such as Mohawk Homeobox (MKX), Brain-type Creatine Kinase (CKB), and FYN Tyrosine Kinase Protooncogene (FYN). The level of methylation in these upstream regions was inversely correlated with the level of gene expression. Thus, differences in DNA methylation patterns likely underlie the discordance in Rett phenotypes between the twins.
Highlights
Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that predominantly affects females with an incidence of one in 10,000–15,000 female births [1,2]
We found that (1) the twins shared the same de novo MECP2 mutation; (2) the de novo mutation was of paternal origin; (3) X chromosome inactivation (XCI) patterns did not differ in various peripheral tissues between the twins; (4) no inter-twin difference was found in whole genome sequences; (5) there were no differences in DNA methylation of the MECP2 promoter region, nor did MECP2 expression differ between the twins; (6) the DNA methylation status of a number of loci varied between the twins; (7) this DNA methylation difference was confirmed by the effect on expression of three genes, which may contribute to clinical differences between the twins
Candidate copy number variants (CNVs) loci identified by a combination of next-generation sequencing and a CNV/single nucleotide polymorphisms (SNPs) chip assay could not be validated by a digital droplet-based PCR quantitative assay
Summary
Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that predominantly affects females with an incidence of one in 10,000–15,000 female births [1,2]. Affected patients manifest various neuro-psychiatric features, including autistic features, epileptic seizures, gait ataxia, and stereotypical hand movements [1]. Mutation of the MECP2 gene (Xq28) accounts for approximately 90% of cases with classic RTT [3]. MECP2 mutations have been confirmed in only two cases, a point mutation (R294X) and a deletion in exon 3, respectively [9,10]. Phenotypic differences between the twins has been attributed to differences in their X chromosome inactivation (XCI) patterns, with skewing in favor of the paternal allele (the presumptive mutated allele) in the twin with the more severe clinical phenotype [9]
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