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Information for genetic management of mtDNA disease: sampling pathogenic mtDNA mutants in the human germline and in placenta

Background Families with a child who died of severe, maternally inherited mitochondrial DNA (mtDNA) disease need information on recurrence risk. Estimating this risk is difficult because of (a) heteroplasmy—the coexistence of mutant and normal mtDNA in the same person—and (b) the so-called mitochondrial bottleneck, whereby the small number of mtDNAs that become the founders for the offspring cause variation in dose of mutant mtDNA. The timing of the bottleneck and of segregation of mtDNA during foetal life determines the management options. Therefore, mtDNA heteroplasmy was studied in oocytes and placenta of women in affected families. Results One mother of a child dying from Leigh syndrome due to the 9176T→C mtDNA mutation transmitted various loads of mutant mtDNA to ≤3 of 20 oocytes. This was used to estimate recurrence as ≤5%. She subsequently conceived a healthy son naturally. Analysis of the placenta showed that some segregation also occurred during placental development, with the mutant mtDNA load varying by >10% in a placenta carrying 65% 3243A→G mutant mtDNA. Discussion This is the first report of (a) an oocyte analysis for preconception counselling, specifically, refining recurrence risks of rare mutations and (b) a widely different load of a pathogenic mtDNA mutation in multiple oocytes, apparently confined to the germline, in an asymptomatic carrier of an mtDNA disease. This suggests that a major component of the bottleneck occurs during oogenesis, probably early in the foetal life of the mother. The variable mutant load in placenta implies that estimates based on a single sample in prenatal diagnosis of mtDNA disorders have limited accuracy.