Long-Read Sequencing for Detection and Subtyping of Prader-Willi and Angelman Syndromes

Prader-Willi (PWS) and Angelman (AS) syndromes are imprinting disorders caused by genetic or epigenetic aberrations of 15q11.2-13.3. Their clinical testing is often multitiered; diagnostic testing begins with methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) or methylation-sensitive polymerase chain reaction (MS-PCR) and then proceeds to molecular subtyping to determine the mechanism and recurrence risk. Currently, correct classification of a proband’s PWS/AS subtype often requires parental samples, a costly process for families and health systems. We investigate genome-wide nanopore sequencing in a cohort of PWS (18) and AS (6) cases as a singular test to detect the molecular subtype, without parental data.