title: Spread of X inactivation on chromosome 15 is associated with a more severe phenotype in a girl with an unbalanced t(X; 15) translocation.
abstract: We report on a baby girl with multiple congenital abnormalities, including cleft palate, intrauterine growth restriction, and double outlet right ventricle (DORV) with ventricular septal defect. She had an unbalanced chromosome translocation t (X;15) resulting in monosomy 15pter → p10 and trisomy Xq13.1 → q28. All three copies of Xq encompass the XIST gene. It is known that X chromosome inactivation could spread to the autosome part of an unbalanced translocation involving chromosome X and an autosome. To confirm the spread of X chromosome inactivation on chromosome 15, we evaluate the methylation change by the HumanMethylation450 BeadChip, a whole genome DNA methylation micorarray that includes 15,259 probes spanning 717 genes on chromosome 15. Results showed there was gain in DNA methylation of more than 20% in 586 CpG sites spanning the long arm of chromosome 15. We further examined the hypermethylated CpG sites located in CpG-island promoter, because genes subjected to X chromosome inactivation will have an increase in DNA methylation level in this region. A total of 75 sites representing 24 genes were hypermethylated. Nearly all of these probes are located in region proximal to the breakpoint, from 15q11.2 to 15q21.3 (35Mb) suggesting that X inactivation was spread to the proximal region of 15q. Gain of DNA methylation, especially in the CpG-island promoter, can result in functional inactivation of genes, and therefore could potentially worsen the phenotype of our patient.
authors.affiliation: Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: K S
authors.initials: KS
authors.lastname: Yeung
authors.forename: Y Y
authors.initials: YY
authors.lastname: Chee
authors.forename: H M
authors.initials: HM
authors.lastname: Luk
authors.forename: Anita S Y
authors.initials: AS
authors.lastname: Kan
authors.forename: Mary H Y
authors.initials: MH
authors.lastname: Tang
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Lau
authors.forename: Andrew Y
authors.initials: AY
authors.lastname: Shuen
authors.forename: Ivan F M
authors.initials: IF
authors.lastname: Lo
authors.forename: Kelvin Y K
authors.initials: KY
authors.lastname: Chan
authors.forename: Brian H Y
authors.initials: BH
authors.lastname: Chung
mesh_terms: D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D010641:Phenotype; D014178:Translocation, Genetic / Q000235:genetics*; D049951:X Chromosome Inactivation / Q000235:genetics*
keywords: DNA methylation; X; X chromosome inactivation; autosome translocation; genome-wide DNA methylation microarray