Long Read Sequencing for the detection of cryptic structural variation and methylome changes in patients with developmental disorders.

Technological improvements over the last decades have been instrumental for the identification of numerous chromosomal anomalies and monogenetic diseases, shedding the light on the extreme genetic heterogeneity underlying developmental disorders. Despite the associated significant increase in diagnostic yield about 40% of patients remain without molecular diagnosis. We hypothesize that cryptic structural variations and methylome anomalies are an important cause of hitherto unsolved cases. Recent reports indicate that this diagnostic gap could be bridged by long-read sequencing (LRS) platforms. In this project, we will determine the accuracy of LRS by using references. In addition, we will chart the genomes of 50 patients with intellectual disability and multiple congenital anomalies but without clinical diagnosis and their parents by nanopore sequencing. We will build the essential but missing reference set of normal structural variation and assess the clinical relevance of identified coding, non-coding and epigenetic variants. We envision a significant increase in the number of patients that will receive a molecular diagnosis and as such, improve patient care and enable preventive and therapeutic opportunities. This study will pave the way to diagnostic implementation of third generation of sequencing.