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    Do genetic factors explain recurrent pregnancy loss?

    We are at the dawn of a new age in the identification of etiologies for both isolated and recurrent pregnancy loss


    Take-home message

    You may suspect that I am obsessed with genetics and you may be wondering why I have not mentioned the role of other putative causes of RPL, including luteal-phase defects, infections, uterine anomalies, and inherited thrombophilias. The bottom line is that I think that, with rare exceptions, these conditions are either unrelated to RPL or they are serendipitous findings. Indeed, we are at the dawn of a new age in the identification of etiologies for both isolated and recurrent pregnancy loss. However, future discoveries concerning RPL are unlikely to come out of relatively crude genome-wide association studies, which, as in the case of many common diseases, have led to only modest correlations with single nucleotide polymorphisms (SNPs).10 Rather, breakthroughs will likely require examination of whole exome and/or genomic sequences of affected POCs with subsequent targeted studies of parental DNA. This approach should lead to identification of a host of autosomal and X-linked recessive causes of intermittent losses, as well as autosomal-dominant disorders of variable penetrance.

    Whole exome and/or genomic sequencing may also commonly detect de novo germ line mutations and copy number variants in the POCs of women with maternal-age-associated recurrent losses found to be “euploid” by karyotype analysis. This would be analogous to the observation of increased rates of genetic abnormalities detected in stillborn specimens using chromosomal microarray studies, which detect far smaller (50 to 100 kb) deletions or duplications, compared with traditional karyotype analysis.11 Exome and genomic sequencing would increase this resolution down to the base pair level. In fact, I would argue that such women have age-induced genetic instability in their oocytes of which karyotype-detected aneuploidy is just the tip of the “genetic” iceberg.


    Charles J Lockwood, MD, MHCM
    Dr Lockwood, Editor-in-Chief, is Dean of the Morsani College of Medicine and Senior Vice President of USF Health, University of South ...

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    • Dr. Robert Knuppel
      Dr. Lockwood makes very important points to help constructively assist patients who generally are grasping at straws for an answer. They are generally offered the expensive testing for answers from non-proven causes. The increase in these very,very low yielding tests has been increasing largely because many offer "answers" and do not say " we simply do not know "and do not reveal the poor positive predictive value of the tests. This plethora of tests are of non-value to the customer and perhaps Lockwood's commentary should be shared with the patient with explanation of the more abstruse terminology.


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