Establishment of genetic diagnosis and genetic counseling of Angelman syndrome.

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Angelman syndrome (AS) is a neurodevelopmental disorder associated with genomic imprinting. AS is caused by functional deficit of the imprinted UBE3A gene located in 15q11-q13. Because several genetic defects could cause UBE3A deficiency, it is important to make proper genetic diagnosis to assess recurrence risk and offer genetic counseling. We have developed the systemic genetic diagnosis system which is composed by DNA metylation analyis, microsatellite polymorphism, imprinting center analysis, and UBE3A mutation screening so that all genetic classes can be diagnosed.We studied 85 Angelman syndrome patients without a common deletion of 15q11-q13, and detected 7 patients with paternal uniparental disomy of chromosome 15, 7 patients with an imprinting defect, and 23 patients with a mutation in UBE3A. Therefore, 67% of deletion-negative Angelman syndrome was diagnosed by the systemic genetic diagnosis system we have developed. All patients with uniparental disomy were sporadic. Imprinting center analysis did not identify a microdeletion of the imprinting center in any of patients with an imprinting defect, therefore these patients was thought to have an epimutation. UBE3A mutations were located in various parts of the gene. Five mutations were located at 3089- 3095 by in exon 16 indicated the hot spot of mutations in Japanese. We examined 8 mothers of patients with a UBE3A mutation, 2 out of 8 mothers carried the same mutation and therefore they were carriers, while 6 mutations arose de novo.Our study should provide important information for genetic counseling of Angelman syndrome in Japanese population.