genetic disorders and Rec abortions.

4) Thrombophilic  Gene   Defects

The    genetic  single defects  in  the group   of inherited  Thrombophilia especially    maternal which have  been associated  with a fetal loss have been  widely reported    but not   without contradiction. Hereditary thrombophilliais  a condition that affects the amount   of a proteins’s  function in the coagulation    system and increases the risk of  thrombosis   . Thrombophilia have been identified as one of the  major cause   of RPL  after  chromosomal abnormalities especially  in the first  half of pregnancy.

Among  the genetic  single defects  mutations  in factor  V Leiden seems to be the most prevalent  and its   relationship   with women   experiencing repeated miscarriages   have been reported by several   studies. But   also RPL   has been   linked to prothrombin gene   mutation protein C and protein S   deficiency  anti thrombin lll  deficiency    and methyitetrahydrofolate reductase mutation  have been reported   by several studies  and meta  analysis . However    nowadays  the association  of some of these gene    mutations and polymorphisms with RPL  is  still open to discussion as some  prospective studies  failed  to support this correlation . Thus   a universal screening   for  inherited   thrombophillia  can be checked  by  analyzing     antiphospholipid syndrome     activated     protein c  resistance serum   fasting homocystine protein  C   protein s  anti thrombin  III prothrombin G 20201A gene mutation and   factor V Leiden in RPL   patients In relation  to the treatment   of anticoagulant agent for the   prevention  of miscarriage in women   with  a history   of at least two  unexplained  miscarriages with or  without inherited   thrombophilia.  However    the analysis  of  most studies  of the past has not been  able to  demonstrate the   beneficial effect of this treatment  and the current guidance   still does not recommend it although it has been suggested   that up to 40%   of American     specialists would  screen in  opposition   of the current   guideline.

 6)   Gentic defect causing Familial Recurrent   Hydatidiform Moles 

Familial recurrent hydatidiform mole is an autosomal recessive condition in which women experience RPL  pre dominantly  classical complete hydatidiform   mole . A   hydatidiform mole is an abnormal    pregnancy characterized    by hydroid placental villi trophoblastic hyperplasia  and poor fetal   development Mutations in two genes   are currently known  to be associated   with FRHM    NLRO7  and KHDC3L being   responsible   for approximately   75%   and 5%    of cases respectively  Both NLRO7  and KHDC3L in normal   pregnancy     and the mechanisms    by which    mutations in these genes   give  rise to complete   hydatidiform mole  remains     controversial   . Although   little is known   about    the  function of KHDC3L   data is emerging   to suggest   that  like other members of NLRP family     of proteins    NLRP7 is  involved in innate immunity leading to the hypothesis that abnormal    immune responses in early   pregnancy underline molar   development in these    conceptions   . In   consonance   with this another group   published    a study in which a tag for SNPs   and haplotype  analysis was used  to investigate  the association   between polymorphisms of NLRP2   and NLRP7   and ididopathic recurrent   miscarriage. They    found that a   tag SNP  of NLRP7  was significantly     associated with  idiopathic    RPL in a recessive  model   while a tag SNP  of NLRP2   showed  marginal  significance codominant  model.

 7) A Other single  Gene Defects related to RPL : But problem how & where to diagnose such single genetic defect??

The genetic variant    rs2305957   has been   related with  recurrent   miscarriage in a recent   study. The common maternal genetic   variant rs2305957 encompassing   the PLK4 gene has been  reported  to contribute    mitotic  origin aneuploidy  risk during human       early   embryo development  aneuploidy  by disrupting centrosome duplication and   mitotic progression during postzygotic cell   divisions. The   study analyzed a total of 2,015    infertile Chinese women who underwent in vitro fertilization and genotyping of  rs2305957   was perforemed  by  means of high resolution melting  analysis. The  authors found that infertile women    carrying the  high risk genotype of rs2305957    formed   fewer morphologic good   quality   Blastocysts and demonstrated  that maternal genetic  variant rs2305957   is a risk factor   for early recurrent  miscarriage.

 7) A meiotic  gene SYCP3 has also been   associated  with  RPL  sycp3 is a well known gene  that encodes   a protein    that plays a critical role in the synsptomemal    complex for  the interaction of homologous chromosomes In a study   published  in 2008   authors   found  in two out of  26  women with RPL  of unknown cause    independent  heterozygous  muclotide alterations in SYCP3 gene   which were   not found in control fertile   patients. The  authors reported that the mutant  proteins interacted with their wild type homolog in vitro and inhibited    the normal formation of SYCP3   protein   fiber. These    data suggest that these mutations are prone to generate an aberrant synaptonemal complex  and   may contribute   to  abnormal   chromosomal behavior    that could lead to recurrent   miscarriages. According    to this a subsequent   case control   study identified a higher genotype frequency   of SYCP3T657C   polymprohism in women with RPL   However  the significant    difference between  allelic and genotype    frequencies   between  groups were not clinically  useful in diagnosing the etiology    of that individual recurrent losses. Therefore    although this   polymorphism    can be considered as a genetic  factor   for pregnancy loss in human   further    functional studies  are required   to support  this .

This  CYP genes   encode a family of proteins that are expressed in placenta   during the first trimester   and some of the members    are related to hormonal    metabolism  and  detoxification systems. A gene polymorphism    of the member   CYP17  has been associated with risks of RPL  by several studies. CYP17   gene encodes the cytochrome P450c17a   enzyme  which  mediates both  steroid 17a   hydroxylase and  17,20   lyase  activities and functions at key steps  in the    genesis   of human sex steroid hormones Scientists    in 2003  reported that a variant of CYP17  may   predispose to an increased risk  of RPL with   a gene dosage  effect. In addition   other genetic   variants of this family polymorphisms of cytochrome P450    17   743542   CYPIAI   rs 1048943   and C?YP2D6   rs 3892097   seem to relate an abnormal    placental function  to the risk of recurrent   miscarriage   as suggested by the findings of a very   recent  meta analysis.

Although    several polymorphisms    and genetic variants   associated  with RPL  have been  reported so far additional  research  is still required  to   identify   not only  new genetic   variants but also  select  those   that remain   controversial   to eventually  be introduced as genetic  markers into the clinical routine.