Noninvasive prenatal diagnosis in a fetus at risk for methylmalonic acidemia

Abstract

PurposePrenatal diagnosis of fetal Mendelian disorders can benefit from non-invasive approaches using fetal cell-free DNA in maternal plasma. Detecting metabolic disorders before birth can result in immediate treatment post partum in order to optimize outcome.MethodsWe developed a mathematical model and an experimental methodology to analyze the case of a fetus with a 25% risk of inheriting two known mutations in MUT which cause methylmalonic acidemia. To accomplish this, we measured allelic counts from the mutation sites and the fetal fraction from high minor allele frequency SNP positions.ResultsBy counting linked alleles, the test was able to distinguish 11 positive markers from the negative controls and thereby determine whether or not the mutations carried by the parents were inherited by the fetus. For a homozygous fetus, the Z-score of the mutation site was 5.97 whereas the median Z-score of all the linked alleles was 4.56 when all negative (heterozygous) controls had a Z-score of <2.5.ConclusionsThe application of this methodology for diagnosing of methlymalonic acidemia shows that this approach is a cost-effective and non-invasive manner in diagnosing known mutations related to Mendelian disorders in the fetus.