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Maternal Folate Receptor Alpha Autoantibodies and Increased Fetal Nuchal Translucency as Potential Early Markers of
Claudio Giorlandino1,2, Katia Margiotti1, Marco Fabiani1
1Human Genetics Lab, Altamedica Main Centre, Rome, Italy.
Purpose:
To investigate the association between increased fetal nuchal translucency (NT) and maternal folate receptor alpha autoantibodies (FRAA) positivity, and to evaluate the subsequent risk of non-syndromic autism spectrum disorder (ASD) in offspring.
Methods:
A total of 3600 first-trimester ultrasounds were screened at a fetal medicine center. Among these, 27 fetuses with markedly increased NT (≥ 3.5 mm) underwent invasive prenatal diagnosis, including karyotyping, CGH array, and postnatally whole-exome sequencing (WES) when standard tests were negative. Maternal serum samples were tested for FRAA using ELISA. Eleven pregnancies with negative genetic testing were followed longitudinally, and neurodevelopmental outcomes in children were assessed up to 36 months using ADOS-2 and DSM-5 criteria.
Findings:
Among the 11 fetuses with negative genetic outcomes, 4 mothers tested positive for FRAA. All four FRAA-positive offspring were later diagnosed with ASD, while only one of the seven FRAA-negative offspring received an ASD diagnosis. FRAA-positive cases exhibited markedly increased NT (≥ 3.5 mm) but no pathogenic genetic variants, suggesting an immune-mediated etiology. FRAA levels persisted in maternal and neonatal serum, implying ongoing exposure during gestation.
Conclusion:
FRAA positivity in pregnancies with isolated markedly increased NT may serve as an early biomarker of increased ASD risk in offspring. These findings support the hypothesis of an immune-metabolic mechanism contributing to ASD and suggest potential preventive interventions such as folinic acid supplementation.
