Imprinting

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct complex disorders mapped to chromosome 15q11-q13.

PWS - paternal deletion. Symptoms Neonatal: hypotonia, Initial feeding difficulties, Developmental delay,Behaviour problems, Hyperphagia by ~ 3 yrs, Short stature, Obesity, Small hands and feet, Almond shaped eyes, Male hypogonadism

AS - developmental delay, speech impairement, ataxia, frequent laughter, microcephaly, seizures, 

PWS genetics- 70% paternal deletion, 30% UPD (two copies of maternal chromosome) 1% imprinting defect (50% risk of reaccurence if defect in imprinting centre) 

AS genetics-70% maternal deletion, 3% paternal uniparental disomy, 4% imprinting defect, 10% UBE3A gene mutation (UBE3A normally active in maternal chromosome and silenced on paternal chromosome)

Why do they occur? The critical region contains several genes that are normally transcriptionally inactive on either the maternal or paternal chromosome, these genes are silenced epigenetically by methylation - a process known as imprinting. This means indiviuals normally only have one active copy of the gene - so if that is deleted then either AS or PWS occurs depending on whether the maternal (AS) or paternal (PWS) is deleted. To investigate imprinting disorders you can use MS-MLPA - methylation specific-multiplex ligation-dependent probe amplification plus aCGH, microsatellite analysis or sequence analysis.