Abstract
Genetic disorders are a frequent cause of hospitalization, morbidity and mortality in pediatric patients, especially in the neonatal or pediatric intensive care unit (NICU/PICU). In recent years, rapid genome-wide sequencing (exome or whole genome sequencing) has been applied in the NICU/PICU. However, mtDNA sequencing is not routinely available in rapid genetic diagnosis programs, which may fail to diagnose mtDNA mutation-associated diseases. Herein, we explored the clinical utility of rapid exome sequencing combined with mtDNA sequencing in critically ill pediatric patients with suspected genetic disorders. Rapid clinical exome sequencing (CES) was performed as a first-tier test in 40 critically ill pediatric patients (aged from 6 days to 15 years) with suspected genetic conditions. Blood samples were also collected from the parents for trio analysis. Twenty-six patients presented with neuromuscular abnormalities or other systemic abnormalities, suggestive of suspected mitochondrial diseases or the necessity for a differential diagnosis of other diseases, underwent rapid mtDNA sequencing concurrently. A diagnosis was made in 18 patients (45.0%, 18/40); three cases with de novo autosomal dominant variants, ten cases with homozygous or compound heterozygous variants, three cases with hemizygous variants inherited from mother, three cases with heterozygous variants inherited from either parent, and one case with a mtDNA mutation. The 18 patients were diagnosed with metabolic (n = 7), immunodeficiency (n = 4), cardiovascular (n = 2), neuromuscular (n = 2) disorders, and others. Genetic testing reports were generated with a median time of 5 days (range, 3–9 days). Thirteen patients that were diagnosed had an available medical treatment and resulted in a positive outcome. We propose that rapid exome sequencing combined with mitochondrial DNA sequencing should be available to patients with suspected mitochondrial diseases or undefined clinical features necessary for making a differential diagnosis of other diseases.
Highlights
Genetic disorders are the leading cause of hospitalization, morbidity and mortality in pediatric patients, especially in the neonatal or pediatric intensive care unit (NICU/Pediatric intensive care unit (PICU)) (Stevenson and Carey, 2004; Willig et al, 2015; French et al, 2019)
We explored the clinical utility of combined rapid clinical exome sequencing (CES) and mitochondrial DNA (mtDNA) sequencing in 40 critically ill pediatric patients with suspected genetic disorders
Of the known genetic diseases according to the database of Online Mendelian Inheritance in Man (OMIM), the majority predominantly affect infants and children, which are the leading cause of infant mortality and pediatric hospital admissions
Summary
Genetic disorders are the leading cause of hospitalization, morbidity and mortality in pediatric patients, especially in the neonatal or pediatric intensive care unit (NICU/PICU) (Stevenson and Carey, 2004; Willig et al, 2015; French et al, 2019). Many traditional diagnostic methods are too slow to provide clinically useful information to physicians. An early and accurate genetic diagnosis would be of great value for the clinical management of the patient and family (Australian Genomics Health Alliance Acute Care Flagship, Lunke et al, 2020; Cakici et al, 2020; Dimmock et al, 2020). For those genetic diseases that can be treated, rapid diagnosis can provide timely interventions and avoid other unnecessary or potentially harmful therapies, reducing mortality and intensive care. For genetic diseases currently lacking effective treatments, the diagnosis may be useful in evaluating prognosis and preventing possible complications, as well as facilitating further genetic counseling for the family
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