MORC2 – Leigh Syndrome

MORC2 has been implicated in Leigh syndrome through limited genetic observations. In a cohort of 219 molecularly confirmed Leigh syndrome patients, next-generation sequencing identified rare MORC2 variants in individual cases, suggesting a possible but uncommon contribution to the disease (PMID:36675121). A separate case report described a female infant with a de novo MORC2 variant, c.262G>C (p.Ala88Pro), who presented with early-onset neurodegeneration, microcephaly, and brain atrophy overlapping Leigh‐like features (PMID:38204468). Furthermore, in a cohort of 20 individuals with MORC2‐related neurodevelopmental disorders, 5 of 18 imaged showed basal ganglia and brainstem lesions reminiscent of Leigh syndrome on MRI (PMID:32693025).

Functional studies provide mechanistic support for MORC2’s role in mitochondrial‐related neurodegeneration. MORC2 pathogenic variants hyperactivate the HUSH complex, altering chromatin compaction and epigenetic silencing in neuronal cells. More recently, a MORC2‐specific DNA methylation episignature was shown to repress NDUFAF2, a key Leigh syndrome gene, establishing a direct mechanistic link between MORC2 dysfunction and the molecular pathology of Leigh syndrome (PMID:40302207).

Key Take-home: Current data indicate a limited but biologically plausible association between heterozygous MORC2 variants and Leigh syndrome, warranting further genetic and functional investigation.

References

• Unknown • 2023 • Clinical and molecular findings of 219 patients with Leigh syndrome PMID:36675121
• Unknown • 2023 • MORC2‐related DIGFAN syndrome presenting with Leigh‐like features PMID:38204468
• American Journal of Human Genetics • 2020 • De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism PMID:32693025
• Brain : a journal of neurology • 2025 • Pleiotropic effects of MORC2 derive from its epigenetic signature PMID:40302207

Evidence Based Scoring (AI generated)