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

Marchington, D., Malik, S., Banerjee, A., Turner, K., Samuels, D., Macaulay, V. , Oakeshott, P., Fratter, C., Kennedy, S. and Poulton, J. (2010) Information for genetic management of mtDNA disease: sampling pathogenic mtDNA mutants in the human germline and in placenta. Journal of Medical Genetics, 47(4), pp. 257-261. (doi: 10.1136/jmg.2009.072900)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Macaulay, Dr Vincent
Authors: Marchington, D., Malik, S., Banerjee, A., Turner, K., Samuels, D., Macaulay, V., Oakeshott, P., Fratter, C., Kennedy, S., and Poulton, J.
College/School:College of Science and Engineering > School of Mathematics and Statistics > Statistics
Journal Name:Journal of Medical Genetics
Journal Abbr.:J. Med. Genet.
ISSN:0022-2593
ISSN (Online):1468-6244
Published Online:12 November 2009

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