PubMed · 4316163
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R Venezia. 1970-05-20. [Karyotyping].. https://pubmed.ncbi.nlm.nih.gov/4316163/
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This paper presents several models for investigating whether the HLA allogenotypes DR1/Br, DR3 and DR10 are genetic markers for a predisposition of experiencing unexplained recurrent foetal losses. A total of 199 women from 113 families answered questionnaires concerning their pregnancies and 145 of these women were HLA typed. The analysis of the data is complicated as dependencies between pregnancy outcomes are expected. The main purpose of the paper is to illustrate how such analyses can be performed using Bayesian graphical models and Gibbs sampling. The analyses are made using the programs BUGS and CODA. Markov chain Monte Carlo analyses within a Bayesian framework have become easier with the introduction of these programs. However, experience shows that some caution is required so we recommend making some initial analyses using very simple models and perhaps approximative methods, followed by a model development introducing increasing complexity.
Methylenetetrahydrofolate reductase (MTHFR) mutations are commonly associated with hyperhomocysteinemia, and, through their defects in homocysteine metabolism, they have been implicated as risk factors for neural tube defects and unexplained, recurrent embryo losses in early pregnancy. Folate sufficiency is thought to play an integral role in the phenotypic expression of MTHFR mutations. Samples of neonatal cord blood (n=119) and fetal tissue (n=161) were analyzed for MTHFR C677T and A1298C mutations to determine whether certain MTHFR genotype combinations were associated with decreased in utero viability. Mutation analysis revealed that all possible MTHFR genotype combinations were represented in the fetal group, demonstrating that 677T and 1298C alleles could occur in both cis and trans configurations. Combined 677CT/1298CC and 677TT/1298CC genotypes, which contain three and four mutant alleles, respectively, were not observed in the neonatal group (P=.0402). This suggests decreased viability among fetuses carrying these mutations and a possible selection disadvantage among fetuses with increased numbers of mutant MTHFR alleles. This is the first report that describes the existence of human MTHFR 677CT/1298CC and 677TT/1298CC genotypes and demonstrates their potential role in compromised fetal viability.
Preimplantation genetic diagnosis (PGD) includes a variety of techniques that have been developed to detect the transmission to the offspring of genetic diseases or of chromosome abnormalities by couples at risk before a pregnancy is established, to avoid these couples the risk of recurrent abortions and/or of repeated terminations of pregnancy. Candidate couples are carriers of gene mutations or of structural chromosome rearrangements, or with recurrent spontaneous abortions of unknown origin. Diagnostic procedures include different modalities of gene amplification using the polymerase chain reaction (PCR) or of fluorescent in situ hybridization (FISH). Embryo biopsies are carried out at the 6-8 cell stage. Healthy embryos are transferred on day 4 or at the blastocyst stage. By now, several hundred healthy children have been born using PGD, and only one diagnostic error has been reported.