GFM2 – Leigh Syndrome

GFM2 encodes a mitochondrial ribosome recycling factor that is essential for proper mitochondrial translation and energy production. Recent evidence has linked GFM2 mutations to Leigh syndrome, a severe neurological disorder, with affected individuals presenting with features such as optic atrophy, arthrogryposis multiplex congenita, and severe intellectual disability (PMID:26016410).

In a well‐documented case report, two female siblings were shown to harbor compound heterozygous variants in GFM2. One of these variants, reported as c.2029-1G>A (p.Ala677LeufsTer2), causes aberrant splicing leading to a premature stop codon. This study provided key segregation data, with both affected siblings demonstrating the same compound heterozygous state, supporting an autosomal recessive inheritance pattern (PMID:26016410).

Genetic evidence across multiple studies further reinforces the association. While the initial case report documented the variants in a familial context, additional multi-patient analyses have revealed similar findings in cohorts of Leigh syndrome patients. The recurrence of deleterious mutations in GFM2 in independent studies underscores the robustness of these genetic observations (PMID:38283147).

Functional assessment studies have provided mechanistic insights into the pathogenicity of GFM2 mutations. Experimental investigations, including splicing assays and evaluations of mitochondrial protein levels, demonstrated that the identified mutations lead to a loss of normal GFM2 function and a consequent defect in oxidative phosphorylation. Such functional data align with the clinical phenotypes observed in patients and highlight a loss-of-function mechanism (PMID:29075935).

The integration of genetic and experimental data places the GFM2-Leigh syndrome association within the strong ClinGen framework. The combination of segregation in affected siblings, replication in independent multi-patient studies, and concordant functional evidence provides a compelling case for the clinical validity of this association. Importantly, this robust dataset not only supports diagnostic decision-making but also demonstrates significant potential for commercial and translational application.

Key Take‑home sentence: GFM2 mutations, particularly those causing aberrant splicing such as c.2029-1G>A (p.Ala677LeufsTer2), represent a strong molecular diagnostic marker for Leigh syndrome, underscoring their clinical utility in both patient management and future research.

References

• Journal of human genetics • 2015 • Compound heterozygous GFM2 mutations with Leigh syndrome complicated by arthrogryposis multiplex congenita PMID:26016410
• Neurogenetics • 2017 • Novel GFM2 variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits PMID:29075935
• Frontiers in genetics • 2023 • Expanding the genetic spectrum of mitochondrial diseases in Tunisia: novel variants revealed by whole-exome sequencing PMID:38283147

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