Abstract Details

Title Whole Exome and Whole Genome Sequencing for the Diagnosis of Mitochondrial Diseases in Critically Ill Children

Topic Child Neurology and Developmental Neurology

Presentation(s) S8 - State-of-the-art Diagnostics in Child Neurology (3:42 PM-3:54 PM)

Poster/Presentation
Number 002

Objective To assess the yield and utility of WGS/WES in the diagnosis of rare mitochondrial disorders in critically ill children.

Background Whole exome sequencing (WES) and whole genome sequencing (WGS) are increasingly used to diagnose mitochondrial diseases. However, the incidence of mitochondrial disease in critically ill patients using WGS or WES remains underreported, and the diagnostic yield of WGS or WES compared to other sequencing methodologies for mitochondrial disease is not well understood.

Design/Methods We conducted a single center retrospective cohort study of all participants under 6 years from 1/1/2018-1/1/2023 with a clinical and/or molecularly confirmed diagnosis of mitochondrial disease. We evaluated the proportion of participants who presented to the neonatal or pediatric ICU and characterized their clinical features and genetic testing results.

Results Of the 22 participants (11 males, 50%) who met inclusion criteria, 12 (54%) presented critically ill; 7 (58%) in the NICU, 5 (42%) in the PICU; 2 (9%) were deceased at time of writing. 19 participants (86%) had confirmed molecular diagnosis (mean age of diagnosis 1.4 years), 11 who were critically ill. Among the 19 participants with a molecular diagnosis, 13 (68%) were diagnosed by WES or WGS platforms that include mtDNA sequencing. 6/19 (32%) had a pathogenic mtDNA variant, while 13/19 (68%) had pathogenic nDNA variants. Of the mtDNA variants identified, 5/6 presented critically ill. Of the 12 critically ill patients, 10 (91%) received a molecular diagnosis on WGS or WES; 6 of these 10 patients (60%) underwent other genetic tests which did not reveal a molecular diagnosis. Of the 10 non-critically ill patients, 3 (30%) received a diagnosis on WGS or WES, 2 (66%) of whom had at least one other genetic test that did not yield a result.

Conclusions WGS/WES has high diagnostic yield in critically ill patients with mitochondrial disease.

Authors/Disclosures
Mallory J. Owen, MD (Rady Children's Hospital) PRESENTER	Dr. Owen has nothing to disclose.
Stephen Kingsmore (Rady Children's Institute for Genomic Medicine)	Stephen Kingsmore has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Third Rock Ventures. Stephen Kingsmore has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AB2 Bio. Stephen Kingsmore has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Illumina. Stephen Kingsmore has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACMGG. Stephen Kingsmore has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Takeda. Stephen Kingsmore has received personal compensation in the range of $500,000-$999,999 for serving as an officer or member of the Board of Directors for Rady Children's Institute for Genomic Medicine. Stephen Kingsmore has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Sidra Medicine. Stephen Kingsmore has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Stephen Kingsmore has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Cold Spring Harbor Press. Stephen Kingsmore has stock in Third Rock Ventures. The institution of Stephen Kingsmore has received research support from Alexion, Amgen, Biomarin, Chiesi, Inozyme, Ionis, Mahzi, Orchard, Sanofi, Rocket, Sarepta, Sentynyl, Travere, Ultragenyx. The institution of Stephen Kingsmore has received research support from NIH. Stephen Kingsmore has received intellectual property interests from a discovery or technology relating to health care. Stephen Kingsmore has received intellectual property interests from a discovery or technology relating to health care.
Richard H. Haas, MD	Dr. Haas has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for SPARC. Dr. Haas has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB Pharma. Dr. Haas has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Various Law Firms. Dr. Haas has stock in Various Companies Stock Trading. The institution of Dr. Haas has received research support from NIH North American Mitochondrial Disease Consortium. The institution of Dr. Haas has received research support from Reneo Pharma. The institution of Dr. Haas has received research support from Astellas Pharma. The institution of Dr. Haas has received research support from Acadia Pharma. The institution of Dr. Haas has received research support from Taysha Gene Therapies. The institution of Dr. Haas has received research support from Tisento Pharma.
Jennifer H. Yang, MD (Rady Childrens Hospital/UCSD)	Dr. Yang has received research support from Pediatric Epilepsy Research Foundation. Dr. Yang has received research support from NIH.

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