Inheritance in each genotype

Imprinting Inheritance:

UBE3A mutations and Imprinting Center Defects can exhibit imprinting inheritance, where a carrier parent can pass the genetic defect to their children without causing any problems. If this female child passes the same genetic defect to her son or daughter, regardless of the sex, that child will have AS. When an AS genetic mechanism is determined to be inherited, genetic testing of family members can usually identify carriers of the genetic defect. As you can imagine, professional genetic counseling is recommended in these situations.

Imprinting Center Defect:

There are two types of imprinting center defects: deletions and non-deletive events. Non-deletive events appear not to be inherited and have a recurrence risk of less than 1%. Most deletions are not inherited, but a significant proportion of them are (i.e., maternally inherited), and these confer a 50% risk of recurrence.

UBE3A Mutations:

A UBE3A mutation can occur:

• spontaneously (e.g., not inherited and without an increased recurrence risk), or

• be maternally inherited and carry a 50% recurrence risk.

UBE3A variants can be new in the egg that produced the person or can be inherited from the mother who also carries the variant. Consequently, testing the mother for the variant is important. If the mother does not have the variant, the chance of a future child having the UBE3A variant that causes AS is less than 1%. This means that at least 99% of the time, future children will not have the UBE3A variant that causes AS. The chance is not zero because there have been rare cases reported where the woman had multiple eggs with the variant or actually carried the variant in some body cells.

If the mother has the UBE3A variant, each child has a 50% chance of inheriting the UBE3A variant and thus having AS, and each child has a 50% chance of inheriting the other UBE3A gene from the mother (which is functional) and not having AS. If the mother has the variant, her siblings and other relatives might also have the variant, and these family members may consider genetic testing to understand the chances for their own children.

Common Chromosome Deletion:

More than 98% of chromosomal deletion cases occur due to a spontaneous event and therefore are not inherited; the recurrence risk is less than 1% for these families. However, 1-2% of deletions occur due to an inherited abnormality in maternal chromosome 15, such as a balanced chromosomal translocation. For most individuals, the deletion of UBE3A and surrounding genes was a random event and NOT inherited from the parents. In fact, the deletion occurs while the mother's eggs are developing, which happens before the mother herself is born. However, in rare cases, the deletion occurs during the formation of the egg due to a chromosomal difference that the mother carries. This chromosomal difference increases the possibility of a deletion occurring when the eggs are produced. Consequently, chromosomal testing of the mother is recommended, including FISH, which helps to rule out inherited abnormalities of chromosome 15.

If the mother undergoes typical chromosomal testing, it is anticipated that the chance of a future child having the deletion that causes AS is less than 1%. This means that more than 99% of the time, future children will not have the deletion that causes AS. The chance is not zero because there have been rare cases reported where the woman had multiple eggs with the deletion or actually carried the deletion in some of her body cells.

Paternally inherited uniparental disomy:

Over 99% of patUPD cases occur as a spontaneous, non-inherited event. Even if an individual has Angelman Syndrome (AS) due to patUPD and has a normal karyotype, a chromosomal analysis of the mother should still be offered to exclude the rare possibility that a Robertsonian translocation or a marker chromosome was a predisposing factor (for example, through the generation of a maternal gamete that was nullisomic for chromosome 15, with subsequent post-zygotic "correction" to paternal disomy).

Individuals with no known mechanism (all 4 mechanisms above ruled out):

For parents of individuals with AS who have apparently normal genetic tests (no evidence of deletion, imprinting defect, UPD, or UBE3A mutation), and thus their children are diagnosed only clinically, the risk of recurrence is unknown. An increased risk seems likely, but probably does not exceed 10%.

Germinal mosaicism:

This term refers to a phenomenon in which a genetic defect is present in the cells of the gonad (ovary in the case of the mother) but not in other cells of the body. This occurrence can lead to errors in risk assessment because a genetic test, for example on the mother's blood cells, will be normal when, in fact, a genetic defect is present in the germ cells of her ovary. Fortunately, germinal mosaicism occurs very rarely. However, it has been observed in AS caused by mechanisms of large chromosomal deletion, deletion of the Imprinting Center, and mutation of the UBE3A gene.