Clinical and genetic analysis of two unrelated patients with Angelman syndrome and novel UBE3A mutations

Objective To explore the genetic cause for two familial Angelman syndrome cases and correlation between the clinical phenotypes and their genetic basis. Methods Karyotyping analysis and microarray assay were carried out to exclude chromosome anomalies and uniparental disomy. The UBE3A gene was analyzed for potential point mutations, deletions, insertions and splice site mutations. Reverse transcription PCR was used to evaluate splicing mutation of the RNA transcripts. Results DNA sequencing showed the proband of family 1 has carried a novel maternal UBE3A splice acceptor site mutation, resulting in a guanine-to-cytosine transversion (IVS15-1G>C). Reverse transcription PCR revealed the proband and his mother both carried heterozygous mutant transcripts with loss of 54 and 59 nucleotides in exon 16, respectively. The proband displayed severe mental retardation, ataxia, seizures and inappropriate laughter. The siblings of family 2 has carried a novel maternal missense mutation in exon 16 of the UBE3A gene (c.2540 C>T). She also presented with mental retardation, absent speech, mild ataxia and inappropriate laughter. Conclusion The novel IVS15-1G>C and c. 2540 C>T mutations of the UBE3A gene probably underlie the AS in the two families. Compared with small-scale mutations, larger fragments mutations can produce more severe phenotypes. Key words: Angelman syndrome; UBE3A gene; Splicing mutation; Missense mutation; Mental retardation