Clinical Information

Prader-Willi syndrome (PWS) is a congenital disorder characterized by a biphasic clinical course. Neonates with PWS are hypotonic, have a weak cry, and are initially poor feeders that improve over time. In later infancy and childhood, individuals with PWS have global developmental delay, short stature, hypogonadism, small hands and feet, and marked hyperphagia leading to obesity. PWS is thought to be due to loss of function of paternally expressed genes, although specific genes have not yet been definitively implicated in the phenotype of PWS.

Etiology of Prader-Willi syndrome:

-Chromosome 15 deletion (15q11-13): approximately 70% to 75%

-Maternal uniparental disomy (UPD): 20% to 30%

-Imprinting defect: 1% to 5%

-Chromosome rearrangement: rare

The phenotype caused by paternal deletions of 15q11-13 and by maternal UPD are generally identical with the exception of relative hypopigmentation being more common in patients with deletion PWS.

Angelman syndrome (AS) is a nonprogressive congenital disorder characterized by more significant developmental delay and intellectual disability, ataxia, seizures, jerky arm movements, macrostomia, tongue thrusting, unprovoked laughter, brachycephaly, and virtual absence of speech. AS is due to loss of function of the maternally expressed gene UBE3A.

Etiology of Angelman syndrome:

-Chromosome 15 deletion (15q11-13): approximately 70% to 75%

-Paternal UPD: approximately 5%

-UBE3A variant: approximately 10%

-Imprinting defect: 2% to 5%

-Chromosome rearrangement: rare

-Unknown: approximately 10%

The phenotype of AS patients with maternal deletions is generally more severe than that associated with paternal UPD or imprinting defects, including a higher rate or severity of microcephaly, seizures, and motor difficulties. Patients with AS caused by paternal UPD or imprinting defects generally show better growth and higher developmental and language abilities.

Both chromosome 15 deletions and UPD most often occur as de novo events during conception, and, thus, recurrence risk to siblings is very low. In rare cases, chromosome 15 deletions and UPD occur as a result of parental translocations or other rare cytogenetic rearrangements, and, in these cases, recurrence risks to siblings are increased.

The recurrence risk associated with imprinting defects is dependent on whether there is an identifiable variant.

UBE3A variants can occur sporadically or be inherited in an autosomal dominant fashion. There is a 50% recurrence risk to siblings in cases of an inherited UBE3A variant.

Due to the complex genetic etiology of PWS and AS and the corresponding variability in recurrence risks, careful cytogenetic and molecular testing and family assessment are necessary to provide accurate genetic counseling.

Initial studies to rule-out PWS or AS should include chromosomal microarray analysis to identify chromosome abnormalities that may have phenotypic overlap with PWS or AS, and methylation-sensitive multiple ligation-dependent probe amplification (MLPA) to identify deletions, duplications, and methylation defects. In cases where methylation-sensitive MLPA suggests either deletion or duplication, fluorescence in situ hybridization (FISH) can be used to confirm type I and type II deletions or characterize the disease mechanism, respectively. In cases where methylation-sensitive MLPA suggests abnormal methylation in the absence of a deletion or duplication, UPD studies can be used to characterize the disease mechanism.

Assessment of patients found to have a deletion in the PWS/AS critical region on routine cytogenetic analysis or chromosomal microarray can include confirmation of the deletion by FISH analysis and MLPA analysis to define parent of origin.

For more information, see Prader-Willi and Angelman Syndromes: Laboratory Approach to Diagnosis.