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Discordant phenotypes in first cousins with UBE3A frameshift mutation
G A Molfetta1, M V R Muñoz, A C Santos
1Department of Genetics, School of Medicine, Ribeirao Preto, USP, Brazil. gamolf@rge.fmrp.usp.br
American Journal of Medical Genetics. Part A
|May 20, 2004
Summary
Angelman syndrome (AS) can be caused by UBE3A gene mutations, leading to varied symptoms even with the same mutation. This study highlights discordant phenotypes and potential mosaicism in a family with an UBE3A frameshift mutation.
Area of Science:
- Genetics
- Neurology
- Developmental Biology
Background:
- Mutations in the UBE3A gene are identified in Angelman syndrome (AS) patients lacking deletions, uniparental disomy, or imprinting defects.
- UBE3A mutations are more prevalent in familial AS cases, typically presenting with consistent phenotypes.
Purpose of the Study:
- To investigate discordant phenotypes in two cousins inheriting the same UBE3A frameshift mutation.
- To explore the phenotypic variability and potential for mosaicism in familial AS.
Main Methods:
- Genetic sequencing to identify the UBE3A mutation (GAGG duplication in exon 10).
- Clinical evaluation of affected individuals, including neurological assessment and brain MRI.
- Pedigree analysis to trace mutation inheritance patterns.
Main Results:
- Two cousins with the identical UBE3A frameshift mutation exhibited discordant phenotypes, ranging from typical AS to a severe presentation resembling cerebral palsy.
- Brain MRI revealed differences, with mild cerebral atrophy in one cousin and severe brain malformation in the other.
- The mutation was transmitted from the grandfather to only two of eight siblings, suggesting possible parental mosaicism.
Conclusions:
- The UBE3A gene mutation can lead to a wide spectrum of phenotypes in Angelman syndrome, including severe brain malformations.
- Brain malformations do not exclude an AS diagnosis.
- Parental mosaicism is a potential factor in the inheritance and presentation of UBE3A mutations in AS.