Long Read Sequencing for the detection of cryptic Structural Variation in patients with intellectual disability and congenital anomalies (CRYPTIC SV)

A correct and early genetic diagnosis is essential for patients with intellectual disability and/or multiple congenital anomalies (ID/MCA). A proper diagnosis avoids a ‘diagnostic odyssey’, is vital for family planning, and enables the initiation of early therapeutic interventions in order to improve the outcome. Technical innovations were always instrumental to delineate (new) genetic syndromes and led to an ever-increasing diagnostic yield. Nowadays, state-of-the-art technologies are based on next-generation (2nd generation) short read sequencing and include standard copy number analysis and whole exome analysis. Despite the current gold standard for molecular testing, up to 40% of patients fall within a diagnostic gap, most likely because used technologies fail to identify small (50 bp) to intermediate (50 kb) structural variations (SVs). Elaborative work on limited patient numbers indicate that these ‘cryptic’ SVs are an important cause of human disease. Recent reports indicate that 3rd generation sequencing platforms leveraging long-read sequencing can accurately detect these SVs. In this project we will clinically validate long-read sequencing for the detection of (cryptic) SVs in patients with unexplained ID/MCA and determine the added diagnostic yield. To achieve this goal, we will perform single molecule real-time sequencing on 50 proband-parent trio families and 10 cases with a complex chromosomal rearrangement that failed to pinpoint the specific molecular defect. Hence, this project will thoroughly validate this novel technology and will bridge the results to a new diagnostic procedure. Ultimately, we aim to introduce this new 3rd generation sequencing technology in the standard genetic workup of patients with idiopathic intellectual disability and congenital anomalies. While this technology is currently expensive, and data analysis challenging due to its novelty, we anticipate that dropping sequencing costs and increasing experience at the (inter)national level will eventually become a reality in the near future.