Poster Presentation Australian Society for Medical Research Annual Scientific Meeting 2016

Mosaic Angelman syndrome diagnosis using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and microarray (#147)

Mark Williams 1 2 3 , Chris Joy 1 , Sam McManus 1 , Ivan McGown 1 , James Harraway 1 , Helen Heussler 2 4
  1. Molecular Genetics Department, Mater Pathology, South Brisbane, QLD, Australia
  2. School of Medicine, The University of Queensland, St Lucia, QLD, Australia
  3. Mater Research, South Brisbane, QLD, Australia
  4. Child Development, Lady Cilento Children's Hospital, South Brisbane, QLD, Australia

Angelman syndrome (AS, OMIM# 105830) is a rare neurodevelopmental disorder. Characteristic clinical features are a severe developmental delay, absent speech, gait ataxia, and a unique behavioural phenotype. This behaviour is a happy demeanour that includes frequent laughter, smiling, and excitability. The genetic mechanisms of AS include: de novo maternally derived deletions of 15q11-q13 (70-75% of cases); pathogenic variants in the maternally-inherited/expressed UBE3A gene (~10% of cases); paternal uniparental disomy of chromosome 15 (UPD; 3-7%); and, imprinting defects affecting the maternal chromosome 15 (2-3%). More than 40% of imprinting defects are mosaic. Patients with mosaic AS have milder or atypical presenting clinical features. Mosaicism can arise through different genetic mechanisms. Presented here are two patients investigated for AS, both who had an atypical clinical presentation that included absences of seizures and ataxia. Additionally, each patient was in the upper percentile for weight, which is uncharacteristic for AS. Using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), each case demonstrated an incomplete loss of methylation on the maternal allele at the 15q11-13 loci. This result is consistent with mosaic AS. The first patient’s SNP microarray identified long continuous stretches of homozygosity (LCSH) on chromosome 15. Combined with the MS-MLPA result, this suggests mosaic uniparental disomy (UPD) for chromosome 15. The second patient had a 46, XY karyotype on SNP microarray. In combination with the MS-MLPA result, this suggests a mosaic imprinting defect. These results confirm a diagnosis of AS in each patient and highlight two different genetic mechanisms resulting in mosaicism.