Publications by authors named "Helen Dolling"
To facilitate early deployment of whole-genome sequencing (WGS) for severely ill children, a standardized pipeline for WGS analysis with timely turnaround and primary care pediatric uptake is needed. We developed a bioinformatics pipeline for comprehensive gene-agnostic trio WGS analysis of children suspected of having an undiagnosed monogenic disease that included detection and interpretation of primary genetic mechanisms of disease, including SNVs/indels, CNVs/SVs, uniparental disomy (UPD), imprinted genes, short tandem repeat expansions, mobile element insertions, copy number calling, and mitochondrial genome variants. We assessed primary care practitioner experience and competence in a large cohort of 521 families (comprising 90% WGS trios).
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- The study aimed to improve the identification of rare single gene disorders in critically ill newborns and children by using whole genome sequencing (WGS) to assist in clinical decisions in NICUs and PICUs.
- Researchers performed WGS on 195 families and found that 21% received a molecular diagnosis, suggesting that traditional methods of predicting genetic conditions based on symptoms were ineffective in most cases (90%).
- The findings from WGS significantly influenced clinical management decisions in over 65% of patients, indicating that rapid genomic testing can be a vital tool for effective treatment and care in intensely ill pediatric populations.
Background: Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation.
Methods: We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients.
Article Synopsis
- Isolated complex I deficiency is a common issue in pediatric mitochondrial diseases linked to genetic mutations in complex I genes, affecting its structure and function.
- Next-generation sequencing has helped diagnose four unrelated children with symptoms suggestive of mitochondrial disorders, identifying bi-allelic variants in the NDUFA6 gene, which plays a key role in complex I assembly.
- Functional tests revealed that the mutations led to defects in complex I assembly in patients' fibroblast cells, but using lentiviral transduction restored normal function, also indicating the formation of a supercomplex with other mitochondrial complexes.