Distinct phenotypes distinguish the molecular classes of Angelman syndrome

BACKGROUND Angelman syndrome (AS) is a severe neurobehavioural disorder caused by defects in the maternally derived imprinted domain located on 15q11-q13. Most patients acquire AS by one of five mechanisms: (1) a large interstitial deletion of 15q11-q13; (2) paternal uniparental disomy (UPD) of chro...

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Bibliographic Details
Published in:Journal of medical genetics 2001-12, Vol.38 (12), p.834-845
Main Authors: Lossie, A C, Whitney, M M, Amidon, D, Dong, H J, Chen, P, Theriaque, D, Hutson, A, Nicholls, R D, Zori, R T, Williams, C A, Driscoll, D J
Format: Article
Language:English
Subjects:
15q11-q13
Adult
Angelman syndrome
Angelman Syndrome - classification
Angelman Syndrome - etiology
Angelman Syndrome - genetics
Angelman Syndrome - physiopathology
Biological and medical sciences
Blotting, Southern
Body Height - genetics
Body Mass Index
Child, Preschool
Chromosome aberrations
Chromosomes
Chromosomes, Human, Pair 15 - genetics
Defects
Deoxyribonucleic acid
DNA
DNA Methylation
DNA Mutational Analysis
Female
Genes
Genomic Imprinting - genetics
Genotype
Genotype & phenotype
genotype-phenotype correlations
Growth Disorders - genetics
Growth Disorders - physiopathology
Humans
Hypotheses
In Situ Hybridization, Fluorescence
Laboratories
Language Development Disorders - genetics
Language Development Disorders - physiopathology
Ligases - genetics
Male
Medical genetics
Medical sciences
Mutation
Mutation - genetics
Obesity
Original
Pathogenesis
Patients
Phenotype
Polymorphism, Genetic - genetics
Psychomotor Performance
Seizures - genetics
Seizures - physiopathology
Studies
Ubiquitin-Protein Ligases
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Summary:BACKGROUND Angelman syndrome (AS) is a severe neurobehavioural disorder caused by defects in the maternally derived imprinted domain located on 15q11-q13. Most patients acquire AS by one of five mechanisms: (1) a large interstitial deletion of 15q11-q13; (2) paternal uniparental disomy (UPD) of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the E3 ubiquitin protein ligase gene (UBE3A); or (5) unidentified mechanism(s). All classical patients from these classes exhibit four cardinal features, including severe developmental delay and/or mental retardation, profound speech impairment, a movement and balance disorder, and AS specific behaviour typified by an easily excitable personality with an inappropriately happy affect. In addition, patients can display other characteristics, including microcephaly, hypopigmentation, and seizures. METHODS We restricted the present study to 104 patients (93 families) with a classical AS phenotype. All of our patients were evaluated for 22 clinical variables including growth parameters, acquisition of motor skills, and history of seizures. In addition, molecular and cytogenetic analyses were used to assign a molecular class (I-V) to each patient for genotype-phenotype correlations. RESULTS In our patient repository, 22% of our families had normal DNA methylation analyses along 15q11-q13. Of these, 44% of sporadic patients had mutations withinUBE3A, the largest percentage found to date. Our data indicate that the five molecular classes can be divided into four phenotypic groups: deletions, UPD and ID patients,UBE3A mutation patients, and subjects with unknown aetiology. Deletion patients are the most severely affected, while UPD and ID patients are the least. Differences in body mass index, head circumference, and seizure activity are the most pronounced among the classes. CONCLUSIONS Clinically, we were unable to distinguish between UPD and ID patients, suggesting that 15q11-q13 contains the only significant maternally expressed imprinted genes on chromosome 15.
ISSN:0022-2593
1468-6244
1468-6244
DOI:10.1136/jmg.38.12.834