Molecular Basis And Implications For Genetic Counseling

Angelman syndrome is divided into five major types:

Type I. De novo interstitial deletions of region 15q11q13 are found in about 70% of all AS cases (Table 1).[7] Similar deletions have been reported in association with Prader-Willi syndrome (PWS), a disorder with different phenotype (see Prader-Willi syndrome). The deleted chromosomal area in AS is of maternal origin in contrast to PWS where the origin of the deletions is paternal.[8] These findings suggested the presence of imprinted genes in the PWS/AS region. The common PWS/AS deletion (see also Prader-Willi syndrome) spans about 4 Mb and is routinely diagnosed by FISH analysis.[9] In cases with the common deletion (Type I a) the recurrence risk is lower than 1%.[10] In less than 1% of all AS cases, referred to as Type I b, chromosomal abnormalities are observed in nonaf-fected parents. Two types of families have been reported: 1) an unbalanced translocation in the affected individual with a balanced translocation in his/her mother. In one such family there were affected children with both AS and PWS depending on the transmitting parent;[11] 2) familial interstitial deletion that is present in the patient, his unaffected mother, and possibly the unaffected grandfather.[12] Such deletions are smaller and do not include the region for PWS—when transmitted from the grandfather to the mother they do not lead to PWS. In Type I b families the estimated recurrence risk is up to 50%.

Type II. Uniparental disomy 15 (UPD-15). About 2-3% of AS cases are the result of paternal UPD-15[13]— inheritance of both chromosomes 15 from the father. It

Fig. 1 Photographs of six 11-33-year-old patients with Angelman syndrome. (From Ref. [5].)

seems that most paternal UPD-15 errors occur during postzygotic divisions.[14] Increased parental age is documented in UPD cases.[15]

Although the recurrence risk for UPD (Type II a) is lower than 1%, cases of AS with paternal UPD-15 have been reported in association with familial translocations involving chromosome 15[16] (Type II b). In such cases the recurrence risk may be increased, but the available information is limited. Type III. Imprinting defects. Genomic imprinting in the PWS/AS region is associated with specific DNA methylation patterns reflecting the chromosome's parental origin (see ''Laboratory Testing''). The methylation patterns are abnormal in both deletion and UPD-AS cases. About 5% of AS patients do not have FISH-identifiable deletions or UPD, but have abnormal methylation patterns lacking methylated (maternally specific) DNA sequences despite the established biparental inheritance. In some cases this imprinting defect is associated with smaller deletions in the region, involving the 5' end of the gene SNRPN.[17] This chromosomal locus referred to as an imprinting center (IC) is involved in the imprinting switch process during gametogenesis, which allows the ''resetting'' of the DNA methylation patterns in the gametes to reflect their parental origin. Two physically separated control centers (minimal regions) were identified within the IC region. An 880-bp sequence is believed to be involved in the paternal-to-maternal imprint switch, and when deleted leads to AS. A 4.3-kb sequence is deleted in PWS families with IC mutations and appears to be involved in the maternal-to-paternal imprint switch.[17] Imprinting center deletions are found in about half of the imprinting defect cases. In families with IC deletions (Type III a) the mothers are unaffected carriers of the deletion and have a 50% chance to have another child with AS.[10] In the imprinting defect cases with no identifiable IC deletions (Type III b) the recurrence risk seems to be low as recurrence has not been observed, but the existing data are limited. It seems likely that Type III b abnormalities occur sporadically and are postzygotic.[18] Such abnormalities were recently reported in association with intracel-lular sperm injection procedures.[19] Type IV. UBE3A mutations. At least 20% of the AS patients have normal methylation patterns. In up to 50% of those cases single-gene mutations of the maternally derived allele of the gene UBE3A, which is located within the AS/PWS chromosomal region, were identified.[20,21] Mutations of UBE3A can produce the entire AS phenotype in contrast to PWS, where deficiencies of more than one gene contribute to the disease phenotype. UBE3A gene mutations are found more frequently in familial than in sporadic cases.[20,21] In familial cases the mother of the affected individual carries a silent mutation and the risk for subsequent pregnancies is 50%. Cases of gonadal mosaicism for UBE3A mutations that may lead to recurrence have been reported in significant proportion of mothers.[21] Such findings prompt caution while providing genetic counseling for families in which the mutation is not identified in the mother, as the recurrence risk may not be lower than 1%.[22] Type V. Unknown. There is no confirmatory laboratory test for the last group of AS patients. Their methylation testing and UBE3A mutation screening are normal. Special effort should be made in this group of patients to rule out different etiologies with similar pheno-


Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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