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Dada, Sarah

University of British Columbia

Neurodevelopmental disorders are a broad set of disorders impacting cognition, motor skills, adaptive behaviours, and communication that impact about 15% of children and adolescents globally. They include autism spectrum disorder as well as imprinting disorders such as Temple syndrome, Prader-Willi syndrome, and Angelman syndrome. Neurodevelopmental disorders encompass overlapping phenotypes and co-morbidities, which thereby make them difficult to diagnose, however the diagnosis of these disorders in a timely manner is critical for long-term quality of life. The diagnosis of autism spectrum disorder is behaviourally based, despite having up to 80% genetic underpinning involving molecular heterogeneity. The diagnosis of imprinting disorders currently relies on the interpretation of several molecular techniques to elucidate the many components which may contribute to disorder, such as methylation aberrations or copy number changes. Using many techniques increases the time to diagnosis and treatment, and incurs cost through repeated diagnostic testing and healthcare specialist time. The use of broader all-in-one techniques would alleviate the burden on the healthcare system and improve quality of care through a rapid and precise diagnosis. In this thesis, I investigate the use of long-read whole genome sequencing for precision diagnosis and subtyping of several neurodevelopmental disorders. Long reads overcome known limitations of next generation short-read whole-genome sequencing within large or complex structural variants and GC-rich repetitive regions. Long reads detect both DNA sequence and methylation, and phase haplotypes. I use long-read sequencing to accurately delineate complex structural variants and determine pertinent DNA methylation patterns, which inform clinical diagnosis of individuals with autism spectrum disorder. I use long-read sequencing to detect imprinting disorders Prader-Willi syndrome, Angelman syndrome, and Temple syndrome, and determine their subtypes by determining parent-of-origin specific defects through haplotype phasing, through the use of known imprinting regions to determine heterodisomy and isodisomy, through the detection of copy number loss, and through the detection of small insertions and deletions. In totality, this thesis demonstrates that long-read sequencing presents as a feasible all-in-one option to detect complex and multi-faceted causes of disorder that are both genetic and DNA methylation based, and can provide rapid and accurate diagnosis and treatment of neurodevelopmental disorders.

Text

2025-04-24

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/90755

Bioinformatics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/