Clinical features of maternal uniparental disomy 14 in patients with an epimutation and a deletion of the imprintedDLK1/GTL2gene cluster

Abstract

Maternal uniparental disomy 14 [upd(14)mat] is associated with a recognizable phenotype that includes pre- and postnatal growth retardation, neonatal hypotonia, feeding problems and precocious puberty. Chromosome 14 contains an imprinted gene cluster, which is regulated by a differentially methylated region (IG-DMR) between DLK1 and GTL2. Here we report on four patients with clinical features of upd(14)mat who show a maternal-only methylation pattern, but biparental inheritance for chromosome 14. In three of the patients loss of paternal methylation appears to be a primary epimutation, whereas the other patient has a paternally derived deletion of -1 Mb that includes the imprinted DLK1-GTL2 gene cluster. These findings demonstrate that the upd(14)mat phenotype is caused by altered expression of genes within this cluster.

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

“…A real-time PCR assay for the promoter region of MEG3 was performed as previously described by Buiting et al 16 Multilocus methylation-specific single nucleotide primer extension (MS-SNuPE)…”

“…[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.…”

Genomic imprinting of DIO3, a candidate gene for the syndrome associated with human uniparental disomy of chromosome 14

“…6 Patients with maternal or paternal UPD of human chromosome 14 (UPD14; named Temple and Kagami-Ogata syndromes, respectively) present with distinct developmental abnormalities, including hydrocephalus, hypotonia, abnormal growth, mental retardation, craniofacial dismorphisms, altered puberty onset, abnormal rib cage and others. 7,8 Several genes within this region, including DLK1 and MEG3, are subject to genomic imprinting, that is, they exhibit a high degree of monoallelic expression. 6 However, it is uncertain whether DIO3 is imprinted.…”

Methylation analysis of 79 patients with growth restriction reveals novel patterns of methylation change at imprinted loci

“…1 A number of imprinting syndromes due to aberrant expression of imprinted genes have been described. These include transient neonatal diabetes (TND), Russell-Silver syndrome (RSS), BeckwithWiedemann syndrome (BWS), Prader-Willi syndrome, Angelman syndrome, Pseudohypoparathyroidism type 1b, maternal (also called Temple syndrome 2 ) and paternal UPD 14 related disorder. Though this list represents diverse phenotypes, there are common features: phenotypically, many are associated with disordered growth; molecularly, each may be caused by aberrant methylation at a differentially methylated region (DMR).…”