Long-read sequencing for pathogenic and novel variation discovery in rare diseases

Abstract

Long-read sequencing (LRS) technologies have rapidly evolved over the years with increased accuracy, throughput, and capacity to detect large complex genomic and epigenomic variations. LRS can therefore potentially be a single unified platform for clinical genetic testing, particularly in rare disease settings, where a large number of patients remain undiagnosed using current iterative technologies. Here, we report clinical strategies to identify pathogenic variants from long-read whole-genome sequencing using funnel down approach, focusing on large deleterious variants and abnormal episignature profiles for known diseases. In a cohort of patients, who remained undiagnosed post-traditional short-read testing, 13% had diagnostic findings using this approach. For the first time, we uncover a novel methylation profile in spinal muscular atrophy patients, opening new avenues for the diagnosis and treatment of this life-threatening condition. This study illustrates the utility of LRS in clinical genetic testing and novel disease variation discovery.

Biography

Ahmad is the Director of the Genomics Center of Excellence at Al Jalila Children’s Hospital and an Associate Professor of Genetics at Mohammed Bin Rashid University of Medicine and Health Sciences, UAE. He completed his doctoral studies in genetics at Dartmouth College, USA followed by a fellowship in molecular diagnostics at Dartmouth Medical School. In 2013, he joined Harvard Medical School, USA, where he completed his clinical molecular genetics fellowship and, in 2015, became board-certified by the American Board of Medical Genetics and Genomics. Prior to joining Al Jalila Children’s Hospital, he was a director in the Division of Genomic Diagnostics at the Children’s Hospital of Philadelphia, and also an assistant professor of Pathology and Laboratory Medicine at the University of Pennsylvania, USA.