Critically unwell infants and children with mitochondrial disorders diagnosed by ultrarapid genomic sequencing

Genet Med. 2025 Jan;27(1):101293. doi: 10.1016/j.gim.2024.101293. Epub 2024 Oct 15.

Abstract

Purpose: To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultrarapid genomic testing as part of a national program.

Methods: Ultrarapid genomic sequencing was performed in 454 families (genome sequencing: n = 290, exome sequencing +/- mitochondrial DNA sequencing: n = 164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria.

Results: A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD after broader analysis. Gene-agnostic analysis led to the discovery of 2 novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another 4 individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation.

Conclusion: Ultrarapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.

Keywords: Mitochondrial disorders; Neonatal; Pediatric; Rapid Genomics.

MeSH terms

  • Child
  • Child, Preschool
  • Critical Illness*
  • DNA, Mitochondrial / genetics
  • Exome Sequencing
  • Female
  • Genetic Testing / methods
  • Genomics / methods
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mitochondrial Diseases* / diagnosis
  • Mitochondrial Diseases* / genetics
  • Mutation / genetics
  • Retrospective Studies

Substances

  • DNA, Mitochondrial