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Noninvasive prenatal diagnosis in a fetus at risk for methylmalonic acidemia.

CPQCC Publication
TitleNoninvasive prenatal diagnosis in a fetus at risk for methylmalonic acidemia.
Publication TypeJournal Article
Year of Publication2014
AuthorsGu W, Koh W, Blumenfeld YJ, El-Sayed YY, Hudgins L, Hintz SR, Quake SR
JournalGenet Med
Date Published2014 Jul
KeywordsAmino Acid Metabolism, Inborn Errors, DNA, Female, Fetus, Gene Frequency, Heterozygote, Homozygote, Humans, Methylmalonyl-CoA Mutase, Models, Theoretical, Mutation, Polymerase Chain Reaction, Pregnancy, Prenatal Diagnosis

PURPOSE: Prenatal diagnosis of fetal Mendelian disorders can benefit from noninvasive approaches using fetal cell-free DNA in maternal plasma. Detecting metabolic disorders before birth can result in immediate treatment postpartum in order to optimize outcome.

METHODS: We 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 that cause methylmalonic acidemia. To accomplish this, we measured allelic counts at the mutation sites and the fetal fraction from high minor-allele-frequency single-nucleotide polymorphism positions.

RESULTS: By 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 <2.5.

CONCLUSION: The application of this methodology for diagnosing methylmalonic acidemia shows that this is a cost-effective and noninvasive approach to diagnosing known mutations related to Mendelian disorders in the fetus.

Alternate JournalGenet Med
PubMed ID24406457
PubMed Central IDPMC4079742
Grant ListDP1 OD000251 / OD / NIH HHS / United States
U01 HL099995 / HL / NHLBI NIH HHS / United States
U01 HL099999 / HL / NHLBI NIH HHS / United States