Predicting recurrence risk of Leigh syndrome using prenatal mtDNA heteroplasmy assessment

Predicting recurrence risk for mitochondrial DNA (mtDNA) disorders is challenging because heteroplasmy levels can shift during development. We examined whether prenatal heteroplasmy measurements predict postnatal outcomes for the pathogenic m.13513G > A variant associated with Leigh syndrome. In a longitudinal family-based study involving three naturally conceived pregnancies, mtDNA heteroplasmy was assessed by chorionic villus sampling at 10-12 weeks of gestation and, when available, amniocentesis at 16 weeks, with follow-up in neonatal and postnatal tissues. Prenatal heteroplasmy levels below ∼30% were associated with unaffected outcomes, whereas an affected sibling exhibited near-homoplasmic variant loads in critical organs. These findings suggest prenatal heteroplasmy assessment may inform recurrence risk for the mtDNA m.13513G > A disorder.