Genetic counseling in Angelman syndrome: The challenges of multiple causes

Abstract

The causal heterogeneity of Angelman syndrome (AS) makes providing information regarding recurrence risk both important and challenging, and may have a dramatic impact on reproductive decision-making for the nuclear and extended family. Most cases of AS result from typical large de novo deletions of 15q11-q13, and are expected to have a low (<1%) risk of recurrence. AS due to paternal uniparental disomy (UPD), which occurs in the absence of a parental translocation, is likewise expected to have a <1% risk of recurrence. Parental transmission of a structurally or functionally unbalanced chromosome complement can lead to 15q11-q13 deletions or to UPD and will result in case-specific recurrence risks. In instances where there is no identifiable large deletion or UPD, the risk for recurrence may be as high as 50% as the result of either a maternally inherited imprinting center (IC) mutation or a ubiquitin-protein ligase (UBE3A) gene mutation. Individuals with AS who have none of the above abnormalities comprise a significant proportion of cases, and some may be at a 50% recurrence risk. Misdiagnoses, as well, can be represented in this group. In light of the many conditions which are clinically similar to AS, it is essential to address the possibility of diagnostic uncertainty and potential misdiagnosis prior to the provision of genetic counseling. Summaries of the different causal classes of AS as an algorithm for determination of recurrence risks are presented.

Clinical and genetic aspects of Angelman syndrome

“…133,135 IIa: In families in which AS is the result of paternal UPD and in which no Robertsonian chromosomal translocation is identified in the proband, the risk to sibs of having AS is Ͻ1%. This risk figure is based on the lack of recurrence among all known cases of UPD in AS with normal chromosomes, the experience with UPD in other disorders, and theoretical consideration regarding the mechanism of UPD.…”

Neurological manifestation and genetic diagnosis of Angelman, Rett and Fragile-X syndromes

“…Os casos resultantes de deleção e de dissomia uniparental têm baixo risco de recorrência (1%); nos casos que decorrem de mutação no gene UBE3A e de mutação no centro de imprinting, herdadas da mãe, o risco de recorrência pode ser tão alto quanto 50% 26 . O potencial do risco de recorrência, e a relação entre a severidade do quadro clínico e a alteração molecular já foram demonstradas, 27 assim como a correlação entre o fenótipo e o genótipo 28 .…”

Genomic imprinting: genetic mechanisms and phenotypic consequences in Prader-Willi and Angelman syndromes

“…The IC deletion group includes familial (up to 50% risk) and sporadic cases, and all non-IC deletion cases are sporadic (Bürger et al, 1997;Saitoh et al, 1997;Buiting et al, 1998b). AS patients with the UBE3A mutation can be sporadic, with a low recurrence risk, or familial with a 50% risk of inheritance from a carrier mother (Stalker and Williams, 1998).…”