Case of the Month: December

Recurrent Pregnancy Loss in a Consanguineous Couple – A Unifying Diagnosis of TREX1-Related Aicardi-Goutières Syndrome-1

Clinical Background

A consanguineous couple in their early thirties presented with a history of recurrent pregnancy loss and multiple adverse pregnancy outcomes. The husband was diagnosed with asthenoteratozoospermia, while the wife’s medical profile included pre-eclampsia, hypertension, hypothyroidism, and a previous atonic postpartum hemorrhage. Their reproductive history was significant: the first pregnancy resulted in a male child with severe intrauterine growth restriction (IUGR) and microcephaly at 28 weeks, who survived for only 1 month and 10 days. The second and third pregnancies ended as missed abortions, raising concerns of an underlying genetic condition.

Antenatal Findings and Adverse Outcomes

The couple’s fourth pregnancy also showed multiple abnormalities on antenatal imaging. Findings included microcephaly, ventriculomegaly, dilated cisterna magna, poor operculization of the Sylvian fissures indicating cortical malformation, echogenic bowel, and signs of fetoplacental insufficiency. Despite the severity of these findings, routine genetic evaluations such as parental karyotyping were normal, and non-invasive prenatal testing (NIPT) reported a low risk for common chromosomal aneuploidies. The contrast between imaging abnormalities and normal screening results suggested a potential monogenic cause.

Genetic Investigation and Molecular Diagnosis

To uncover the underlying etiology, whole exome sequencing (WES) was performed on the product of conception from the fourth pregnancy. This revealed a homozygous pathogenic TREX1 variant (c.58dup; p.Glu20GlyfsTer80), confirming the diagnosis of Aicardi-Goutières Syndrome-1 (AGS1), a rare autosomal recessive neuroinflammatory disorder. AGS1 is characterized by excessive interferon signaling, leading to early-onset neurodevelopmental damage, severe fetal growth restriction, placental dysfunction, and poor perinatal outcomes. The pattern of IUGR, microcephaly, cortical malformations, missed abortions, stillbirth, and neonatal death across the couple’s pregnancies strongly aligned with the known prenatal manifestations of AGS1.

Correlation of Clinical Features with AGS1

The severe recurring phenotypes across multiple pregnancies can be explained by the in-utero onset of TREX1-related AGS1. Excess interferon activity associated with this disorder results in fetal neuroinflammatory injury, placental insufficiency, and growth restriction. This pathophysiology offers a unifying explanation for the repeated pregnancy losses, stillbirth, and early neonatal death experienced by this couple. Although later-onset forms of AGS1 exist, the couple’s presentation is consistent with the more severe prenatal form.

Parental Carrier Status and Recurrence Risk

Subsequent parental testing confirmed that both partners were heterozygous carriers of the TREX1 pathogenic variant, indicating an autosomal recessive inheritance pattern. This confers a 25% recurrence risk in each future pregnancy. Identification of carrier status allowed the couple to understand the genetic basis of their reproductive challenges and provided clarity regarding future reproductive risks.

Genetic Counseling and Future Planning

With a confirmed diagnosis, the couple received focused genetic counseling regarding reproductive options, including preimplantation genetic testing for monogenic disorders (PGT-M) and the importance of early prenatal diagnostic testing in future pregnancies. As no curative treatment exists for AGS1, management remains supportive, making early diagnosis and informed reproductive planning crucial for optimizing outcomes.

Conclusion

This case highlights the importance of advanced molecular testing—particularly whole exome sequencing—in evaluating recurrent pregnancy loss when routine investigations are inconclusive. Identifying a rare, definitive monogenic cause such as TREX1-related AGS1 allows for precise diagnosis, individualized counseling, and informed reproductive decision-making. It underscores the essential role of genomics in modern prenatal care and reproductive medicine.