Prader–Willi syndrome and Angelman syndrome

Abstract

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurogenetic disorders in which imprinted genes on the proximal long arm of chromosome 15 are affected. Although the SNORD116 gene cluster has become a prime candidate for PWS, it cannot be excluded that other paternally expressed genes in the chromosomal region 15q11q13 contribute to the full phenotype. AS is caused by a deficiency of the UBE3A gene, which in the brain is expressed from the maternal allele only. The most frequent genetic lesions in both disorders are a de novo deletion of the chromosomal region 15q11q13, uniparental disomy 15, an imprinting defect or, in the case of AS, a mutation of the UBE3A gene. Microdeletions in a small number of patients with PWS and AS have led to the identification of the chromosome 15 imprinting center (IC). The IC consists of two critical elements, which act in cis to regulate imprinting in the whole chromosome 15q11q13 imprinted domain.

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.…”

“…[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. 69,70 The SNRPN gene has a number of alternative transcripts, and AS-imprinting center overlaps with exons of such transcripts.…”

“…A de novo interstitial deletion affecting the entire imprinted domain, and a maternal uniparental disomy are the major causes of PWS (B70% and B25-30%, respectively), and about 1-3% of PWS is caused by abnormal imprinting. 40,66 A small proportion of PWS patients with an imprinting defect carry a deletion at the PWS-imprinting center that lies at the promoter/exon 1 of SNRPN (Figure 2). 66 However, most imprinting defects represent primary epimutations derived from the paternal grandmother.…”

“…40,66 A small proportion of PWS patients with an imprinting defect carry a deletion at the PWS-imprinting center that lies at the promoter/exon 1 of SNRPN (Figure 2). 66 However, most imprinting defects represent primary epimutations derived from the paternal grandmother. This suggests that, unlike other diseases, incorrect erasure of the imprint in the paternal primordial germ cells might have resulted in inheritance of a chromosome carrying an imprinting defect in such patients, 66 but the factor involved in such defects is not clear.…”

Insights into the Genetic Foundations of Human Communication

“…Children affected by severe ID and/or ASD are generally born to healthy parents, and accordingly de novo chromosomal translocations and aneuploidy are major causes of these disorders (van Bokhoven 2011). Other modes of inheritance consistent with sporadic disorder are autosomal recessive, X-linked, and imprinting, and examples of all of these are also found for severe ID (des Portes 2013; Musante and Ropers 2014;Buiting 2010). Recently, sequencing of probands and parents has confirmed that single de novo protein-altering mutations are also causal in a significant proportion of cases (Gilissen et al 2014;Krumm et al 2014;Veltman and Brunner 2012).…”