Recurrent Non Immune Fetal Hydrops Associated With IPEX                     Syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a clinical syndrome associated with mutations in FOXP3 and consequent abnormalities of T regulatory cells. Affected males typically die in infancy or early childhood from a variety of autoimmune conditions. Reports of recurrent pregnancy loss of male fetuses in these families have been accompanied by descriptions of nonimmune fetal hydrops, with or without additional fetal anomalies. Here, we report an additional family affected by IPEX with a novel mutation leading to recurrent second trimester fetal hydrops and intrauterine fetal demise with associated fetal anomalies. This report underscores how careful genetic and pathologic analysis of even midtrimester fetuses can provide important information impacting an entire family. It also further substantiates the use of broad, symptom-targeted genetic screening panels in cases of recurrent pregnancy loss even in the absence of a remarkable pedigree.

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Whole-Genome Sequencing Reveals Exonic Variation of ASIC5 Gene Results in Recurrent Pregnancy Loss

Frontiers in Medicine ◽

10.3389/fmed.2021.699672 ◽

2021 ◽

Vol 8 ◽

Author(s):

Nourah H. Al Qahtani ◽

Sayed AbdulAzeez ◽

Noor B. Almandil ◽

Norah Fahad Alhur ◽

Hind Saleh Alsuwat ◽

...

Keyword(s):

Ion Channel ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Interaction Analysis ◽

Novel Mutation ◽

Direct Sequencing ◽

Recessive Mutation ◽

Whole Genome

Family trio next-generation sequencing-based variant analysis was done to identify the genomic reason on unexplained recurrent pregnancy loss (RPL). A family (dead fetus and parents) from Saudi Arabia with an earlier history of three unexplained RPLs at the ninth week of pregnancy was included in the study. Whole-genome sequencing (WGS) of a dead fetus and the parents was done to identify the pathogenic variation and confirmed through Sanger sequencing. WGS of dead fetus identifies a novel homozygous exonic variation (NM_017419.3:c.680G>T) in ASIC5 (acid-sensing ion channel subunit family member 5) gene; the parents are heterozygous. Newly designed ARMS PCR followed by direct sequencing confirms the presence of heterozygous in one subject and absence of homozygous novel mutation among randomly selected healthy Saudis. The second family with heterozygous was confirmed with three unexplained RPLs. Pathogenicity analysis of R227I amino acid substitution in ASIC5 protein through molecular docking and interaction analysis revealed that the mutations are highly pathogenic, decrease the stability of the protein, and prevent binding of amiloride, which is an activator to open the acid-sensing ion channel of ASIC5. The identified rare and novel autosomal recessive mutation, c.680G>T:p.R227I (ASIC5Saudi), in two families confirm the ASIC5 gene association with RPL and can be fatal to the fetus.

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Characterisation of peri-implantation endometrial Treg and identification of an altered phenotype in recurrent pregnancy loss

Mucosal Immunology ◽

10.1038/s41385-021-00451-1 ◽

2021 ◽

Author(s):

Ingrid Granne ◽

Mengni Shen ◽

Helena Rodriguez-Caro ◽

Gurmeher Chadha ◽

Elizabeth O’Donnell ◽

...

Keyword(s):

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

T Regulatory Cells ◽

Immune Memory ◽

Regulatory Cells ◽

Treg Population ◽

Transcriptomic Signature ◽

Normal Women ◽

Implantation Period ◽

Regulatory Phenotype

AbstractRecurrent Pregnancy Loss (RPL) affects 2–4% of couples, and with increasing numbers of pregnancy losses the risk of miscarrying a euploid pregnancy is increased, suggesting RPL is a pathology distinct from sporadic miscarriage that is due largely to lethal embryonic aneuploidy. There are a number of conditions associated with RPL including unspecified “immune” pathologies; one of the strongest candidates for dysregulation remains T regulatory cells as depletion in the very early stages of pregnancy in mice leads to pregnancy loss. Human endometrial Treg and conventional CD4T cells were isolated during the peri-implantation period of the menstrual cycle in normal women. We identified an endometrial Treg transcriptomic signature and validated an enhanced regulatory phenotype compared to peripheral blood Treg. Parous women had an altered endometrial Treg transcriptome compared to nulliparity, indicating acquired immune memory of pregnancy within the Treg population, by comparison endometrial conventional CD4T cells were not altered. We compared primary and secondary RPL to nulliparous or parous controls respectively. Both RPL subgroups displayed differentially expressed Treg gene transcriptomes compared to controls. We found increased cell surface S1PR1 and decreased TIGIT protein expression by Treg in primary RPL, confirming the presence of altered Treg in the peri-implantation RPL endometrium.

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Characterisation of peri-implantation endometrial Treg and identification of an altered phenotype in recurrent pregnancy loss

10.1101/2021.04.22.21255931 ◽

2021 ◽

Author(s):

Ingrid Granne ◽

Mengni Shen ◽

Helena Rodriguez-Caro ◽

Gurmeher Chadha ◽

Elizabeth O’Donnell ◽

...

Keyword(s):

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

T Regulatory Cells ◽

Acquired Immunity ◽

Regulatory Cells ◽

Treg Population ◽

Transcriptomic Signature ◽

Normal Women ◽

Implantation Period ◽

Regulatory Phenotype

AbstractRecurrent Pregnancy Loss (RPL) affects 2-4% of couples, and with increasing numbers of pregnancy losses the risk of miscarrying a euploid pregnancy is increased, suggesting RPL is a pathology distinct from sporadic miscarriage that is due largely to lethal embryonic aneuploidy. There are a number of conditions associated with RPL including unspecified ‘immune’ pathologies, one of the strongest candidates for dysregulation remains T regulatory cells as depletion in the very early stages of pregnancy in mice leads to pregnancy loss.Human endometrial Treg and conventional CD4T cells were isolated during the peri-implantation period of the menstrual cycle in normal women. We identified an endometrial Treg transcriptomic signature and validated an enhanced regulatory phenotype compared to peripheral blood Treg. Parous women had an altered endometrial Treg transcriptome compared to nulliparity, indicating acquired immunity memory of pregnancy within the Treg population, by comparison endometrial conventional CD4T cells were not altered. We compared primary and secondary RPL to nulliparous or parous controls respectively. Both RPL subgroups displayed differentially expressed Treg gene transcriptomes compared to controls. We found increased cell surface S1PR1 and decreased TIGIT protein expression by Treg in primary RPL, confirming the presence of altered Treg in the peri-implantation RPL endometrium.

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