Genetics of Recurrent Miscarriage: Challenges, Current Knowledge, Future Directions

Abstract

Recurrent miscarriage (RM) occurs in 1–3% of couples aiming at childbirth. Due to multifactorial etiology the clinical diagnosis of RM varies. The design of genetic/“omics” studies to identify genes and biological mechanisms involved in pathogenesis of RM has challenges as there are several options in defining the study subjects (female patient and/or couple with miscarriages, fetus/placenta) and controls. An ideal study would attempt a trio-design focusing on both partners as well as pregnancies of the couple. Application of genetic association studies focusing on pre-selected candidate genes with potential pathological effect in RM show limitations. Polymorphisms in ∼100 genes have been investigated and association with RM is often inconclusive or negative. Also, implication of prognostic molecular diagnostic tests in clinical practice exhibits uncertainties. Future directions in investigating biomolecular risk factors for RM rely on integrating alternative approaches (SNPs, copy number variations, gene/protein expression, epigenetic regulation) in studies of single genes as well as whole-genome analysis. This would be enhanced by collaborative network between research centers and RM clinics.

Association between functional polymorphisms of Foxp3 and Interleukin-21 genes with the occurrence of recurrent pregnancy loss in Gaza strip-Palestine

“…1 Although many known causes of RPL including anatomic (15%), infectious (1%-2%), hormonal (20%), immunological (20%), and genetic (2%-5%) have been identified, a significant number of cases (approximately 40%-50%) do not have known causes, and these cases are called unexplained recurrent pregnancy losses. 2 In the face of unknown etiological factor(s), dysregulated immunity was proposed as a potential mechanism underlying unexplained RPL. 3 This reportedly includes autoimmune abnormalities (e.g., positive antiphospholipid, anti-nuclear and anti-microsomal antibodies), increased cell-mediated immunity and altered T helper Th1-Th2-Th17-Treg balance.…”

Immunogenetic contributions to recurrent pregnancy loss

“…communication between mother and fetus via the placenta and decidua. Disruption or abnormalities in this signaling can result in loss of the pregnancy [10].…”

Paternal Lymphocyte Alloimmunization in the Treatment of Infertility: A New Look at an Old Problem

“…Это означает, что отсутствие БФ может быть обусловлено причинами, не связанными со сходством супружеских пар по аллоантиге-нам. Действительно, если ранее предполагалось, что низкая реактивность лимфоцитов женщины к аллоантигенам партнера в СКЛ и дефицитом БФ у женщин с привычным невынашиванием неясного генеза ассоциированы со сходством супружеских пар по антигенам гистосовмести-мости [7,17], то ряд более поздних исследований не подтвердил однозначность этих предположе-ний [21,32]. Как известно, генерация блокирующих фак-торов отражает активацию гуморального иммун-ного ответа против фетальных аллоантигенов, и этот процесс может в значительной степени усиливаться на фоне Th1→Th2 переключения или генерации регуляторных Т-клеток, подавля-ющих клеточный иммунитет.…”