Prader Willi (PWS; OMIM #176270) and Angelman (AS; OMIM #105830) syndromes are clinically distinct genetic disorders, both mapping to chromosome region 15q11-q13.
PWS is the most common genetic cause of obesity, owing to an involuntary urge to eat constantly coupled with a reduced need for calories. Additional non-specific symptoms are short stature, mental retardation, incomplete sexual development and behavioural problems. In infancy, PWS is characterised by severe hypotonia and feeding difficulties – both common conditions which make clinical diagnosis difficult.
AS is characterised by severe mental retardation, microcephaly, seizures, characteristic abnormal behaviours – including apparent happy demeanour and hand-flapping movements – facial appearance and severe speech limitations. Delayed onset of specific features means that clinical diagnosis is difficult in the first two to three years of life.
The incidence of each syndrome is approximately 1 in 15 000, but may be underestimated due to the difficulty of clinical diagnosis, with either relatively non-specific findings particularly in infancy, or clinical overlap with many other disorders.
Genetic testing for PWS and AS has become the standard diagnostic method since clinical criteria, though defined, are not always specific. Moreover the number of genetic tests performed for PWS and AS is significantly higher than the number of positively diagnosed cases.
However, the complexity of genetic testing for PWS and AS is itself compounded by the underlying atypical genetics – chromosome region 15q11-q13 contains an ‘imprinted region’, whereby genes from the chromosome pair are unequally expressed. The level of expression is determined by the parental origin of the chromosome. Imprinting of the genes within chromosome region 15q11-q13 is under control of an ‘imprinting centre’ which regulates gene expression through epigenetic changes including methylation. The genes associated with PWS are usually only expressed on the paternally-inherited chromosome 15 whilst the maternally-inherited genes are inactivated.
Conversely, the gene or genes associated with AS – including UBE3A – are usually only expressed on the maternally-inherited chromosome 15 whilst the paternally-inherited genes are inactivated. Loss of gene function can be due to a genetic deletion in the chromosome 15q11-q13 region, uniparental disomy – inheritance of both copies of a chromosome or part of a chromosome from only one parent – or an imprinting centre defect. AS can additionally result from a mutation in the UBE3A gene.
There are several testing methods for the cytogenetic or molecular diagnosis of PWS and AS, the most common being DNA-based methylation testing for abnormal methylation in the chromosome 15q11-q13 region. This method will detect more than 99% of PWS individuals and approximately 80% of AS individuals. Sequence analysis of the UBE3A gene will detect a further approximate 10% of individuals with AS.
The panel comprises six human genomic DNA samples to cover a range of Prader Willi and Angelman syndrome genetic defects. Samples are presented as 5 µg freeze dried genomic DNA in glass ampoules. The collaborative validation study data indicates that these materials are suitable for use in methylation-specific multiplex ligation-dependent probe amplification, methylation-specific PCR and UBE3A sequencing
UBE3A point mutation
paternal uniparental disomy or imprinting centre defect
Prader Willi syndrome
maternal uniparental disomy
B Array CGH
The panel was validated in an international collaborative study and the genotypes confirmed by the use of methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), methylation-specific PCR (MS-PCR), UBE3A sequence analysis, Southern blotting, microsatellite analysis, methylation-sensitive PCR, DHPLC and methylation-specific melting analysis.
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Dr Ross Hawkins - Principal ScientistDr Jennifer Boyle – Principal ScientistDr Pia Sanzone – Senior ScientistMr Malcolm Hawkins - Senior Scientist Dr Leandro Lo-Cascio - Senior ScientistMr Miltiades Stylianou – ScientistMr Noble Ossai - Scientist
09/140: WHO International Genetic Reference Panel, Prader Willi and Angelman Syndromes, Human gDNAOther genomic reference materials