Diagnosis:
Prader-Willi and Angelman syndromes
• Genomic imprinting is a form of epigenetic inheritance in which certain loci are marked differently (usually with DNA methylation, but also with histone modifications, and so on) in maternal and paternal alleles, resulting in differential expression of the two alleles. Therefore, the mutation’s effect is affected by parent of origin, unlike classic Mendelian inheritance.
• Maternally imprinted genes are paternally expressed, and paternally imprinted genes are maternally expressed.
• The clinically distinct Prader-Willi and Angelman syndromes involve the same locus on 15q11-13; a deletion of this locus on the paternal chromosome causes Prader-Willi syndrome and on the maternal chromosome causes Angelman syndrome.
• The imprinted domain in this locus contains a number of centromeric genes that are paternally expressed and maternally imprinted, and two telomeric genes that are maternally expressed, including UBE3A.
• Approximately 70% of cases of Prader-Willi syndrome and Angelman syndrome are caused by a de novo large deletion in this locus: Prader-Willi syndrome in the paternal and Angelman syndrome in the maternal allele. About 25% to 30% of cases of Prader-Willi syndrome are caused by maternal uniparental disomy and 1% to 2% of cases of Angelman syndrome by paternal uniparental disomy. These have a recurrence rate of less than 1%.
• Approximately 1% of cases of Prader-Willi syndrome and 2% to 4% of cases of Angelman syndrome are caused by an imprinting defect. When these are the result of an inherited imprinting center deletion (rare), the recurrence risk in siblings is 50%.
• Approximately 2% to 5% of cases of Angelmansyndrome are caused by inactivating mutations of UBE3A in a maternal allele; if this mutation is present in the mother, the recurrence risk in siblings is 50%.
• The SNRPN promoter is methylated and inactive in the maternal allele and unmethylated and active in the paternal allele; this is the basis for Southern blot testing with a methylation-sensitive enzyme and an SNRPN probe, or methylation-specific/-sensitive polymerase chain reaction (PCR) testing. Additional tests include testing for UBE3A mutations and testing for small interstitial deletions of the imprinting center. The latter two are important because of the high recurrence risk in siblings. Less than 1% of cases of Prader-Willi syndrome, but almost 15% to 20% of cases of Angelman syndrome, have no identifiable molecular cause.
• Other genetic conditions that involve imprinted loci include Beckwith-Wiedemann syndrome, an overgrowth syndrome involving imprinted loci on 11p15.5; Russell-Silver syndrome with growth retardation, relative macrocephaly, and a “triangular face,” associated with maternal uniparental disomy of chromosome 7 or hypomethylation of 11p15.5 and/or other imprinted loci; and transient neonatal diabetes mellitus type 1, involving imprinted genes on chromosome 6q24.
• Imprinted loci have been identified on human chromosomes 6, 7, 11, 14, and 15; about 60 imprinted human genes are known.
