Project Summary/Abstract
The goal of this proposal is to improve upon current methods to identify genetic contributors to rare diseases,
especially neurodevelopmental disorders (NDDs) in children. Finding such variants is both of fundamental
biological value and has potential clinical relevance to the affected individuals and their families. To improve
upon current approaches, a DNA sequencing platform from Pacific Biosciences, called “HiFi”, will be used.
Preliminary data suggest that HiFi can reveal disease-relevant genetic variants that were missed by standard
genome sequencing approaches. Genomes of 500 affected individuals will be sequenced using HiFi, and for
200 of them, their parents will also be sequenced (900 total genomes sequenced). This process will be optimized
to balance data quality, accuracy, and costs. Comprehensive maps of genetic variation and de novo genome
assemblies will be generated for each individual using a variety of methods, which will be systematically
benchmarked and improved. These results will be analyzed to identify variants in the proband that may be
causally related to their symptoms using commonly accepted standards for clinical interpretation of genomic
data. Variants found to be relevant for a particular proband’s symptoms will be validated with orthogonal testing
and returned to families by a genetic counselor, if such return is deemed appropriate by the referring clinician.
This study will address a major challenge in human genetics, and potentially lead to a fundamental change in
the way human genome sequencing is performed in both research and clinical settings.
