Angelman syndrome (AS), also known as angel syndrome or happy puppet syndrome, is a neurodevelopmental disorder caused by a defect in the imprinted gene on maternal chromosome 15, q11-13. Newborns usually have a normal phenotype, with developmental delays appearing as early as around six months of age and typical features not usually apparent until after one year of age. Patients present clinically with severe mental retardation, microcephaly, ataxia, atypical laughter, epilepsy, impaired speech development, water preference, and sleep disturbances. Currently, the incidence of AS is reported to be about 1/15,000-1/20,000 in foreign countries, and the results of research studies suggest that there are significant differences in the incidence of AS in different populations. At present, there is no systematic study on the incidence of AS in Chinese population. The UBE3A gene is localized in the AS key region 15q11-13, contains 16 exons, covers a genome of about 120 kb, encodes a ubiquitin protein ligase consisting of 865 amino acids with a relative molecular mass of 100,000, and its expression is tissue-specific and restricted to brain tissue. The UBE3A gene is maternal in origin, i.e., the UBE3A gene from the mother is expressed, its deletion leads to AS, and the UBE3A gene from the father is methylated and not expressed. Current studies suggest that four clear mechanisms lead to the development of AS: a. Maternal deletion (75%): a large segment of 4-6 Mb is missing in the key region of maternal chromosome 15q11.2-13 in the UBE3A gene region, resulting in the absence of expression of this maternal UBE3A gene; b. Paternal uniparental diploidy (1-2%): paternal UPD on chromosome 15, thus lacking the maternal UBE3A gene, and the paternal UBE3A gene is not active for expression; c. Cases with imprinting defect (3%): abnormal imprinting status of the maternal 15q11.2-13 region, causing abnormal UBE3A gene expression; d. Mutations in the maternal UBE3A gene (5-10%), which cannot be expressed normally. All four mechanisms directly or indirectly cause low or no expression of the UBE3A gene; the pathogenicity is unknown in 10-15% of cases. Angelman syndrome and Prader-Willi syndrome share the same pathogenic compartment, 15q11-q13, except that Angelman syndrome is caused by a maternal 15q11-q13 deletion, whereas Prader-Willi syndrome is caused by a paternal 15q11-q13 deletion. The clinical diagnosis of AS is based on typical clinical manifestations, and the main criteria are as follows: 1. Patients with AS have normal head circumference before and at birth, without major birth defects; 2. Delayed development without skill loss; 5. Language impairment with little or no use of words, receptive language skills and nonverbal communication skills over verbal skills; 6. Motor or balance disorders with generalized ataxia or/and limb tremors; 7. Laboratory diagnosis is the only method to confirm the diagnosis, especially in the early stages of the disease and in patients with atypical symptoms. Laboratory diagnosis is the only method to confirm the diagnosis, especially in the early stage of the disease and in patients with atypical symptoms. 1. DNA methylation analysis Patients with AS are affected by deletion of q11.2-13 region 5-7Mb of chromosome 15, uniparental disomy (UPD) or imprinted gene defect and only one side is unmethylated (abnormal biparental specific methylation imprinting). It is important to note that most commercially available DNA methylation analysis tests are not able to distinguish whether AS is caused by chromosomal fragment deletions, uniparental disomy (UPD) or imprinted gene defects (ID). Therefore, some new methods including pyrophosphate sequencing, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), sequence-based quantitative methylation analysis (SeQMA) and other methods of copy number analysis have been put into application as to understand the pathogenic mechanism of AS. 2. Fluorescence in situ hybridization (FISH) and microarray comparative genomic hybridization (array CGH) The detection rate of patients with deletions of 5-7 Mb in the q11.2-13 segment of chromosome 15 can reach 68% by FISH, array CGH or other deletion detection methods (see Table 1). 3. Analysis of uniparental disomy (UPD). DNA polymorphism analysis using DNA samples from family patients with prior evidence and both parents to detect uniparental dimorphism (UPD) has a detection rate of about 7%. 4, imprinting center analysis imprinting deletion in about 3% of patients, patients generally have abnormal DNA methylation imprinting but fluorescence in situ hybridization (FISH) or microarray comparative genomic hybridization (array CGH) analysis is normal and no evidence of uniparental disomy (UPD). Approximately 10-20% of patients with imprinted deletions are caused by microdeletions (6-200 kb) including the AS imprinting center (IC). These microdeletions can be detected using multiple methods of deletion analysis (see Table 1). Another 80-90% of patients with imprinted deletions (IDs) are thought to be the result of epigenetic mutations during maternal oogenesis or early embryogenesis. 5. Sequence analysis When DNA methylation tests are normal in patients with clinical features of AS, analysis of their UBE3A gene sequence should be considered. Approximately 11% of AS patients have typical UBE3A gene mutations. A minority of patients with AS have multiple exons or deletions of the entire UBE3A gene. This can be detected using various methods of deletion analysis (see Table 1). In addition to this, some microarray comparative genomic hybridization techniques can be applied to detect these deletions. Genetic counseling Patients with AS are at risk for family members as follows: parents of the presentee. The parents of the preclear are not affected. Whether or not the parents of the proband are recommended for genetic testing depends on the pathogenic mechanism of this AS patient. Risk of recurrence: less than 1% if deletion or UPD; 50% if imprinted center or UBE3A mutation. Progeny of prior evidence. To date, only one case of AS patient has been reported to give birth. Consideration of risk for offspring suggests professional genetic counseling. Other family members of the preclear. If the mother of a preclear is tested for an imprinting defect or mutation in the UBE3A gene, the mother’s sisters are also at risk for imprinting defects or mutations. Any child of an unaffected sister has a 50% chance of developing AS. Uncles of unaffected preclears will not have children with AS, but their grandchildren are at risk of developing AS.