Priscillia Siswara1, Nadine Taubenheim1, Elizabeth M. Algar1,2
1 Genetics and Molecular Pathology Laboratory, Monash Health, 246 Clayton Road, Victoria, 3168
2 Hudson Institute of Medical Research, 27-31 Wright Street, Victoria, 3168
Disorders of genomic imprinting are rare developmental disorders in which either the maternal or paternal allele, is monoallelically expressed. Imprinting is conserved in mammals and constitutes part of a higher order system of gene regulation to control the expression of developmentally critical genes. Imprinting is maintained in locus control regions by several mechanisms including CpG methylation, histone acetylation/deacetylation and antisense transcription. The Genetics and Molecular Pathology laboratory at Monash Health provides genetic testing for human imprinting disorders including Beckwith-Wiedemann syndrome (BWS), Russell-Silver syndrome (RSS), Prader-Willi syndrome (PWS), Angelman syndrome (AS), and Albright hereditary osteodystrophy (AHO) using methylation specific MLPA (MS-MLPA®). In four years the laboratory has been referred 794 cases for 11p15.5 imprinting centre 1 and 2 (IC1 and IC2) testing, 67 cases for SNRPN (15q11) testing, and four cases for GNAS (20q13.32) investigation. Common 11p15 alterations in BWS were detected in 110 cases including 5 with H19 hypermethylation, 77 with KCNQ1OT1 loss of methylation (LOM), 27 with uniparental isodisomy (UPD), one with a CDKN1C mutation and three had copy number variations (CNVs). In RSS, 36 cases were positive for H19 LOM. Mosaicism presents a challenge in ascertaining BWS and RSS. MS-MLPA® is only able to detect to a lower limit of 20% mosaicism for UPD 11p15. SNP array testing is recommended in test negative cases with clinical features. A diagnosis was confirmed by methylation analysis in 12% of referred cases with suspected PWS or AS where the parental origin of the deleted chromosome or UPD was established. None of four cases with AHO were positive for GNAS abnormalities. MS-MLPA® is an efficient method for identifying imprinting defects in these disorders, however has some limitations including sensitivity towards sample quality, sample source and a comparatively high limit of detection.
Priscillia Siswara is a medical scientist at the Genetics and Molecular Pathology Laboratory, Monash health. She did her undergraduate degree at University of Washington, Seattle and holds a masters degree in laboratory medicine from Royal Melbourne Institute of Technology.