J Med Genet 2001;38:834-845 ( December )

Distinct phenotypes distinguish the molecular classes of Angelman syndrome

A C Lossie^{* a b}, M M Whitney^a, D Amidon^a, H J Dong^a, P Chen^c, D Theriaque^d, A Hutson^{c d}, R D Nicholls^e, R T Zori^a, C A Williams^a, D J Driscoll^{a b}

^a R C Philips Unit and Division of Genetics, Department of Pediatrics, University of Florida, Gainesville, FL, USA, ^b Center for Mammalian Genetics, University of Florida, Gainesville, FL, USA, ^c Division of Biostatistics, Department of Statistics, University of Florida, Gainesville, FL, USA, ^d GCRC, University of Florida, Gainesville, FL, USA, ^e Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

Correspondence to: Dr Driscoll, Pediatric Genetics, Box 100296, University of Florida College of Medicine, Gainesville, FL 32610-0296, USA, driscdj{at}peds.ufl.edu

Revised version received 14 August 2001; Accepted for publication 26 August 2001

BACKGROUNDAngelman 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.
METHODSWe 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.
RESULTSIn our patient repository, 22% of our families had normal DNA methylation analyses along 15q11-q13. Of these, 44% of sporadic patients had mutations within UBE3A, 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.
CONCLUSIONSClinically, 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.


Keywords: Angelman syndrome; genotype-phenotype correlations; DNA methylation; 15q11-q13

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^* Present address: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA

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© 2001 by J Med Genet
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