Establishment of the first WHO international genetic reference panel for Prader Willi and Angelman syndromes

Overview & Synopsis

Prader Willi and Angelman syndromes are clinically distinct genetic disorders both mapping to chromosome region 15q11-q13 which are caused by a loss of function of paternal or maternally inherited genes in the region, respectively. With clinical diagnosis often difficult, particularly in infancy, confirmatory genetic diagnosis is essential to enable clinical intervention. However, the latter is challenged by the complex genetics behind both disorders and the unmet need for characterised reference materials to aid accurate molecular diagnosis. With this in mind, a panel of six genotyping reference materials for Prader Willi and Angelman syndromes was developed, which should be stable for many years and available to all diagnostic laboratories. The panel comprises three Prader Will syndrome materials (two with different paternal deletions, and one with maternal uniparental disomy) and three Angelman syndrome materials (one with a maternal deletion, one with paternal uniparental disomy or an epigenetic imprinting centre defect, and one with a point mutation). Genomic DNA was bulk extracted from Epstein-Barr virus transformed lymphoblastoid cell lines established from consenting patients, and freeze-dried as aliquots in glass ampoules. Thirty seven laboratories from twenty six countries participated in a collaborative study to assess the suitability of the panel. Participants evaluated the blinded, triplicate materials using their routine diagnostic methods against in-house controls or externally-sourced uncertified reference materials. The panel was established by the Expert Committee on Biological Standardization of the World Health Organization as the 1st International Genetic Reference Panel for Prader Willi & Angelman Syndromes.