LabPLUS is part of Auckland District Health Board
and provides medical laboratory testing
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MOLECULAR GENETICS TESTS - PRADER-WILLI AND ANGELMAN SYNDROME |
| Background: Prader-Willi Syndrome (PWS) is a congenital disorder characterised by a biphasic clinical course. Neonates with PWS are hypotonic, have a weak cry and are poor feeders but 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. In about 70-75% of individuals with classic PWS, a chromosome 15 deletion (15q11.2k-q13) can be detected using high resolution chromosome analysis and newer molecular cytogenetic techniques (FISH). By molecular genetic studies, the deleted chromosome 15 has been shown to be on the paternal chromosome and usually arises by a new mutation. Twenty percent of individuals with classic PWS do not have the deletion, but instead have received two copies of chromosome 15 from their mother and none from their father. This is called "maternal uniparental disomy". Again, these individuals are deficient for paternally derived genes from chromosome 15. The phenotype caused by paternal deletions of 15q11.2-q13 and by maternal uniparental disomy are generally identical with the exception of relative hypopigmentation being more common in patients with deletion PWS. Rare patients with PWS show neither maternal uniparental disomy or deletion of 15q11.2-q13, the cause being attributed to point mutations and cryptic chromosomal anomalies. Angelman syndrome (AS) is a non-progressive congenital disorder characterised by more significant developmental delay/mental retardation, ataxia, jerky arm movements, macrostomia, tongue thrusting, unprovoked laughter, brachycephaly, and virtual absence of speech. AS has also been associated with two different types of chromosome 15 abnormalities. About 65-80% of affected individuals have a de novo deletion of essentially the same region of chromosome 15 detected for PWS. The deletion can be demonstrated by high resolution chromosome analysis in conjunction with FISH analysis. Molecular genetic testing has shown that the AS deletion occurs only on the chromosome 15 inherited from the mother. Thus, the individuals with AS resulting from deletion or uniparental disomy are deficient for maternally derived genes from chromosomes 15. Both chromosome 15 deletions and uniparental disomy occur as de novo events during conception, and thus recurrence risk to siblings is very low. No chromosomal or DNA abnormality has been identified in the remainder of clinically diagnosed AS patients (15-25%). These patients may have point mutations or tiny deletions that cannot be detected by current methodologies. In some families, AS may be transmitted as an autosomal recessive disorder with a 25% recurrence risk in siblings of affected individuals. A familial form due to a dominant gene at 15q11.2-q13 has also been described. Thus, careful cytogenetic, molecular testing and family assessment is necessary to provide accurate genetic counselling. For comprehensive laboratory assessment of the patient suspected of having PWS or AS, initial studies should include high resolution cytogenetic analysis to identify large deletions or other chromosome abnormalities which may have phenotypic overlap with PWS or AS, and Southern blot analysis, to identify uniparental disomy or parent of origin of deleted material. In cases where no cytogenetic deletion is evident, but Southern blot analysis suggests either uniparental disomy or deletion, fluorescence in situ hybridisation (FISH) can be used to discriminate between uniparental disomy and submicroscopic deletion. Assessment of patients found to have a deletion in the PWS/AS critical region on routine cytogenetic analysis will include confirmation of the deletion by FISH analysis and Southern blot analysis to define parent of origin. Analysis:
PW71b probe detects: 90% of Prader Willi Syndrome casesKB17 probe detects: 95% of Prader Willi Syndrome casesIndications for Testing:
Blood: 3 x 4.0mL whole blood into EDTA tubes . Invert several times to mix. Forward within 24-48 hours at ambient temperature. Paediatric Samples: Minimum of 3mL whole blood in EDTA tubes. Prenatal Samples:
Paraffin blocks of tissue are also acceptable. The tissue sample should not have had prolonged immersion in formalin before embedding. NOTE:
6 weeks once sample is received. Cost of test: Angelman Syndrome - $473.13 Prader Willi Syndrome - $509.14 Note: Prices excludes GST (12.5%) and may change without notice. Please click on a link below to view information about another specific test.
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