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.