Epimutations in Prader-Willi and Angelman Syndromes: A Molecular Study of 136 Patients with an Imprinting Defect

Abstract

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurogenetic disorders that are caused by the loss of function of imprinted genes in 15q11-q13. In a small group of patients, the disease is due to aberrant imprinting and gene silencing. Here, we describe the molecular analysis of 51 patients with PWS and 85 patients with AS who have such a defect. Seven patients with PWS (14%) and eight patients with AS (9%) were found to have an imprinting center (IC) deletion. Sequence analysis of 32 patients with PWS and no IC deletion and 66 patients with AS and no IC deletion did not reveal any point mutation in the critical IC elements. The presence of a faint methylated band in 27% of patients with AS and no IC deletion suggests that these patients are mosaic for an imprinting defect that occurred after fertilization. In patients with AS, the imprinting defect occurred on the chromosome that was inherited from either the maternal grandfather or grandmother; however, in all informative patients with PWS and no IC deletion, the imprinting defect occurred on the chromosome inherited from the paternal grandmother. These data suggest that this imprinting defect results from a failure to erase the maternal imprint during spermatogenesis.

Clinical and genetic aspects of Angelman syndrome

“…2), varying in size from 6 to 200 kb, have been found between the PW71 locus and the SNRPN gene in individuals with both AS and PWS. 105,106 The smallest deletion of the IC region common among this subset of AS cases has been narrowed to 880 base pairs, 108 which is approximately 30 kb proximal to the smallest IC region deletion common among PWS cases. Most individuals with AS caused by IC defects do not have a deletion of the AS IC region, but rather have epigenetic defects that disrupt IC function.…”

“…Even though these individuals have biparental inheritance of chromosome 15, the maternal 15q11.2-q13 region has a paternal epigenotype and is therefore transcriptionally incompetent for the maternal-only expressed gene(s) in this region. [105][106][107] Microdeletions in the IC (Fig. 2), varying in size from 6 to 200 kb, have been found between the PW71 locus and the SNRPN gene in individuals with both AS and PWS.…”

Prader-Willi syndrome

“…Germ cell mosaicism in the father is a rare but distinct possibility and has been observed in cases of 15q11.2 deletions 159 and IC deletions. 123,160 In addition, recurrent meiotic nondisjunction of maternal chromosome 15 has been observed. 161 FISH, array comparative genomic hybridization, DNA methylation analysis, MS-MLPA, and DNA polymorphism studies for UPD have been validated in prenatal diagnosis, but only DNA methylation analysis (including MS-MLPA) at the 5′ SNRPN locus will identify the IDs.…”

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

“…64,65 AS is usually associated with genetic abnormalities at an imprinted cluster containing UBE3A within 15q11-q13, and approximately 2-4% of the patients show epigenetic defects at this region, which include loss of methylation at the ICR at an imprinted bicistronic transcript encoding small nuclear ribonucleoprotein N (SNRPN) and SNRPN upstream reading frame (SNURF) (referred to as SNRPN) (Figure 2 and Table 1). [66][67][68] Among those, 92% are thought to have epigenetic mutations occurring in either oocytes or early embryos. 66 Maternally transmitted deletions of a region located 35 kb upstream of the SNRPN ICR, along with loss of methylation, have been identified in AS patients, which led to the discovery of the AS-imprinting center.…”