CHOP Researchers Lead International Expert Panel, Curating Evidence for Over 100 Genes Causing Leigh Syndrome Spectrum

An international group led by researchers at Children’s Hospital of Philadelphia (CHOP) has characterized gene-disease relationships for more than 100 genes associated with Leigh syndrome spectrum, the most common pediatric form of mitochondrial disease. This multi-year project involving detailed evidence curation and expert panel review creates a strong consensus among the mitochondrial disease research community to facilitate diagnosis, development of new therapeutic options, and clinical trial enrollment for patients affected by this disease.

The project findings were recently published online by the journal Annals of Neurology.

Mitochondrial disease consists of a group of disorders characterized by dysfunction of the mitochondria, the energy-producing “batteries” of our cells, which may result in a variety of complex symptoms throughout the body. Leigh syndrome spectrum disorder is the most common form of mitochondrial disease, occuring in about 1 in 40,000 births. It is even more common in certain populations, with particularly higher incidences in the Faroe Islands and the Saguenay Lac-Saint-Jean region of Quebec, and can also be diagnosed in adulthood.

While many genes have been linked to Leigh syndrome since its first description in 1951, there has not always been clear consensus about which genes are responsible for symptoms in certain patients. This has led to certain diseases being characterized as Leigh-like syndrome, although this diagnosis has been applied inconsistently. Currently, these disorders are more broadly characterized as falling within a Leigh syndrome spectrum, based on their similar clinical and biochemical overlap.

Elizabeth McCormick, MS, LCGC “As we broaden our understanding of Leigh syndrome spectrum, confirming the strength of available evidence to support the relationship between which genes are linked to this disease and how they cause symptoms in patients is critical to making sure we are improving the diagnostic accuracy,” said the study’s first author Elizabeth McCormick, MS, LCGC, a certified genetic counselor, senior research coordinator in the Mitochondrial Medicine Frontier Program at CHOP, and lead author on this study.

To characterize as many gene-disease relationships within Leigh syndrome spectrum as possible, a group of 40 international primary mitochondrial disease experts came together in 2017 to form the Clinical Genome (ClinGen) Resource Mitochondrial Disease Gene Curation Expert Panel (Mitochondrial Diseases Gene Curation Expert Panel - ClinGen | Clinical Genome Resource). The group met monthly for four years to first establish Leigh syndrome spectrum curation criteria with guidance and support from the Precision-FDA approved ClinGen resource program, and then rigorously curate the published literature and review gene-disease relationships for Leigh syndrome spectrum, ultimately establishing evidence for association with Leigh syndrome spectrum for 112 of 114 gene-disease relationships reviewed, with one gene being reviewed twice.

After an extensive literature review by gene biocurators and expert panel discussions of evidence identified for each gene, the researchers reached consensus to determine that 31 genes were considered “definitive” in terms of their relationship with Leigh syndrome spectrum, 38 had moderate gene-disease relationships, and 43 had a limited relationship. Ultimately, while two additional genes had been previously been described as being linked to Leigh syndrome spectrum, there was not convincing evidence found at this time to confirm the causal relationship. These included both genes in the nuclear genome as well those in the genome within our cell’s mitochondria.

Marni Falk, MD “This critical work could not have happened without the remarkable dedication of the global mitochondrial disease research community coming together to make sure we are ultimately able to establish the most accurate genetic diagnoses for our patients,” said senior study co-author Marni Falk, MD, a Clinical Geneticist, Professor of Pediatrics, and Executive Director as well as attending physician in the Mitochondrial Medicine Frontier Program at CHOP. “This study provides us with a framework for making more accurate clinical genetic diagnostic laboratory tests and clinical diagnoses, which is essential to improve clinical management and personalized therapeutic approaches for Leigh syndrome spectrum. Consensus agreement of the causal genes is also essential to guide eligibility guidelines to enroll the appropriate patients in relevant clinical trials of precision medicine being developed for Leigh syndrome spectrum.”

This study was supported by National Institutes of Health grant U24-HD093483 (Multi-PIs, Marni J. Falk, MD and Xiaowu Gai, PhD) as well as Great Ormond Street Hospital Children’s Charity, the Lily Foundation and the National Institute of Health Research Great Ormond Street Hospital Biomedical Research Centre. The authors would like to thank the ClinGen Gene Curation Working Group and Clinical Domain Working Group Oversight Committee for their detailed review, suggestions, and approval of this Mito Gene Curation Expert Panel. Additional work remains actively underway to complete expert curation of all primary mitochondrial disease genes.

McCormick et al, “Expert panel curation of 113 primary mitochondrial disease genes for the Leigh syndrome spectrum.” Ann Neurol. Online May 31, 2023. DOI: 10.1002/ana.26716.