Differentially methylated regions in maternal and paternal uniparental disomy for chromosome 7

Abstract

DNA methylation is a hallmark of genomic imprinting and differentially methylated regions (DMRs) are found near and in imprinted genes. Imprinted genes are expressed only from the maternal or paternal allele and their normal balance can be disrupted by uniparental disomy (UPD), the inheritance of both chromosomes of a chromosome pair exclusively from only either the mother or the father. Maternal UPD for chromosome 7 (matUPD7) results in Silver-Russell syndrome (SRS) with typical features and growth retardation, but no gene has been conclusively implicated in SRS. In order to identify novel DMRs and putative imprinted genes on chromosome 7, we analyzed eight matUPD7 patients, a segmental matUPD7q31-qter, a rare patUPD7 case and ten controls on the Infinium HumanMethylation450K BeadChip with 30 017 CpG methylation probes for chromosome 7. Genome-scale analysis showed highly significant clustering of DMRs only on chromosome 7, including the known imprinted loci GRB10, SGCE/PEG10, and PEG/MEST. We found ten novel DMRs on chromosome 7, two DMRs for the predicted imprinted genes HOXA4 and GLI3 and one for the disputed imprinted gene PON1. Quantitative RT-PCR on blood RNA samples comparing matUPD7, patUPD7, and controls showed differential expression for three genes with novel DMRs, HOXA4, GLI3, and SVOPL. Allele specific expression analysis confirmed maternal only expression of SVOPL and imprinting of HOXA4 was supported by monoallelic expression. These results present the first comprehensive map of parent-of-origin specific DMRs on human chromosome 7, suggesting many new imprinted sites.

Symmetrical Dose-Dependent DNA-Methylation Profiles in Children with Deletion or Duplication of 7q11.23

“…For example, the imprinted homeobox 4A (HOXA4 [MIM: 142953]) 50 showed consistent hypermethylation only in the WS group, but the methylation levels in the Dup7 group were indistinguishable from those in the TD control group ( Figure S6A). In contrast, HOXB7 (MIM: 142962) showed hypomethylation in the Dup7 group, but no significant increase in methylation was seen in the WS group ( Figure S6B).…”

Genome-wide methylation analysis of retrocopy-associated CpG islands and their genomic environment

“…The ancestral gene also contains a CGI, but this is unmethylated. As demonstrated by oocytespecific methylation, maternal methylation in blood cells, hypermethylation in maternal uniparental disomy 7 (matUPD7 29 ), and loss of methylation in 4 of 6 patients with MLID, the RPS2P32 associated CGI is maternally imprinted. However, we found biallelic expression of RPS2P32 in blood, although there may be a slight skewing of allelic expression of the reverse strand (Fig.…”

“…Also, Hannula-Jouppi et al did not find a significantly different expression between matUPD7 and controls. 29 At first sight, this excludes RPS2P32 as a novel imprinted gene, but it is possible that it is monoallelically expressed in other tissues.…”

Paternal Uniparental Disomy of Chromosome 14 with Hypospadias

“…Uniparental heterodisomy involves 2 different homologous chromosomes (inherited from both grandparents) from one parent being transmitted to the offspring, indicating a meiosis I error, while uniparental isodisomy involves 2 identical, replica copies of a single homologue of a chromosome, indicating either a meiosis II error or postzygotic chromosomal duplication [Shin et al, 2016]. The phenotypes characteristic of UPD are generally considered to be due to the presence of imprinted genes on the chromosomes involved, as UPD has been associated with trisomy mosaicism or homozygosity of autosomal recessively inherited mutations [Tohyama et al, 2011;Haudry et al, 2012;Hannula-Jouppi et al, 2014]. Imprinting effects likely cause the phenotypic abnormalities characteristic of the distinctive malformation complex observed in patUPD14 syndrome.…”