Epimutation (hypomethylation) affecting the chromosome 14q32.2 imprinted region in a girl with upd(14)mat-like phenotype

Abstract

Maternal uniparental disomy for chromosome 14 (upd(14)mat) causes clinically discernible features such as pre-and/or postnatal growth failure, hypotonia, obesity, small hands, and early onset of puberty. The monoallelic expression patterns at the 14q32.2 imprinted region are tightly related to methylation status of the DLK1 -MEG3 intergenic differential methylation region (DMR) and the MEG3-DMR that are severely hypermethylated after paternal transmission and grossly hypomethylated after maternal transmission. We examined this imprinted region in a 2 2/12-year-old Japanese patient who was born with a normal birth size (length, þ 0.2 SD; weight, À0.5 SD) and showed postnatal growth failure (height, À3.1 SD; weight, À3.4 SD), hypotonia, frontal bossing, micrognathia, and small hands. Methylation analysis, genotyping analysis, and deletion analysis were performed with blood samples of the patient and the parents, showing that the DMRs of this patient were grossly hypomethylated in the absence of upd(14)mat and deletion of the DMRs. The results indicate the occurrence of an epimutation (hypomethylation) affecting the normally methylated DMRs of paternal origin, and imply that epimutations should be examined in patients with upd(14)mat-like phenotype.

Epigenetic Deregulation of Genomic Imprinting in Humans: Causal Mechanisms and Clinical Implications

“…In these studies, loss of methylation was detected at the ICR (the intergenic germlineDMR) and also at the DMR comprising the MEG3 pro moter, indicating the occurrence of an epimuta tion (hypomethylation) affecting both of these paternally methylated DMRs [46][47][48].…”

“…Epigenetic deregulation of genomic imprinting in humans Review Several recent reports described deletions and epimutations affecting the imprinted DLK1 DIO3 region at chromosome 14q32.2 in individu als with a phenotype similar to that of maternal UPD of chromosome 14 (but who did not pres ent evidence for the occurrence of UPD) [46][47][48]. In these studies, loss of methylation was detected at the ICR (the intergenic germlineDMR) and also at the DMR comprising the MEG3 pro moter, indicating the occurrence of an epimuta tion (hypomethylation) affecting both of these paternally methylated DMRs [46][47][48].…”

The IG-DMR and the MEG3-DMR at Human Chromosome 14q32.2: Hierarchical Interaction and Distinct Functional Properties as Imprinting Control Centers

“…(B) Cases with upd(14)mat-like phenotype. Epimutation-2: Hypomethylation of the IG-DMR and the MEG3 -DMR of paternal origin (Temple et al [5], Buiting et al [6], Hosoki et al [7], and Zechner et al [8]). Deletion-4: Microdeletion involving DLK1 , the two DMRs, and MEG3 on the paternally inherited chromosome (cases 9 and 10 in Kagami et al [2]).…”

Novel deletions affecting the MEG3-DMR provide further evidence for a hierarchical regulation of imprinting in 14q32

“…[11][12][13] In both syndromes, three types of molecular alterations have been reported: uniparental disomy, deletions and epimutations. 7,[14][15][16][17][18][19] In contrast to uniparental disomy and epimutations, deletions affecting regulatory elements in 14q32 on the maternal or the paternal allele are associated with a highrecurrence risk. 7,19 It has been shown that both the MEG3-and the IG-DMR function as imprinting control centers in the placenta and the body.…”