PC1101: Genomic Evaluation for Mitochondrial Disease in 1,935 Infants

Background: Mitochondrial disease is the largest class of inborn errors of metabolism and can affect multiple organ systems at different ages. In this study, we focus on mitochondrial disease phenotypes and genotypes in infants who have undergone rapid DNA sequencing. As more NICUs are utilizing this technology, it remains an open question if one should also include rapid mitochondrial DNA testing. This study evaluates the incidence of mitochondrial disease caused by both nuclear (n-DNA) and mitochondrial DNA (mt-DNA) in NICU patients.

Methods: This study is a retrospective review of 1,935 infants who received rapid exome sequencing, which included 721 (37%) infants who also received concurrent mt-DNA sequencing and deletion testing by whole mitochondrial genome amplification. n-DNA variants from rapid exome sequencing were classified according to ACMG/AMP guideline (PMID 25741868). Variants from mt-DNA were classified according to specifications of the ACMG/AMP guidelines for mt-DNA variant interpretation (PMID: 32906214). The positive results were compared with all the known mitochondrial disease genes as well as the genes in MitoCarta 3 to determine the association with mitochondrial diseases. Human Ontology Phenotypes (HPO) terms extracted from the medical records of each infant were recorded and compared with the genetic testing results.

Results: The average age of the overall cohort was 2.2 months and the median age was 1.1 months. Male to female ratio was 1.2. Overall, 674/1,935 (35%) infants had positive findings (likely pathogenic/pathogenic variants) in n-DNA and of these, 108 (16%) infants had diagnostic results in nuclear genes associated with mitochondrial function. The nuclear gene most frequently involved with mitochondrial dysfunction was POLG (5/1,935). The most common phenotypes in positive n-DNA cases were hypotonia (40%), lactic acidosis (38%), seizure (36%), hypoglycemia (23%), and respiratory distress (25%). Mt-DNA testing was done in 721 (37%) of infants, in addition to n-DNA testing. Eight infants (1.1%) had pathogenic mt-DNA variants with heteroplasmy levels that confirmed the diagnosis of mt-DNA diseases. The average age of these 8 infants was 3 months and 75% were male. Two additional infants had homoplasmic variants in MT-RNR1 m.1555 A>G, which conveys a risk for aminoglycoside induced deafness. Fourteen (1.9%) infants had pathogenic/likely pathogenic variants in mt-DNA and associated mitochondrial disease phenotypes; however, the heteroplasmy levels were too low to confirm causality without testing additional tissues. The most common phenotypes in diagnostic positive mt-DNA cases was lactic acidosis (88%), seizure (50%) and hypotonia (38%).

Conclusion: Mitochondrial disease is not an uncommon presentation in infants receiving rapid DNA sequencing. Although mt-DNA testing has a lower yield than n-DNA testing, it must be considered in NICU infants with mitochondrial disease associated signs to include hypotonia, lactic acidosis, seizures, hypoglycemia, and respiratory distress