Transgenerational Effects and Heritability of Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorder

Frye, Richard E.; Cohen, Ira L.; Sequeira, Jeffrey M.; Hill, Zoe; Espinoza, Alina; Brown, W. Ted; Mevs, Clifford; Marchi, Elaine; Flory, Michael; Jenkins, Edmund C.; Velinov, Milen T.; Quadros, Edward V.

doi:10.3390/ijms26178293

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Transgenerational Effects and Heritability of Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorder

by

Richard E. Frye

^1,*

,

Ira L. Cohen

²,

Jeffrey M. Sequeira

³,

Zoe Hill

¹,

Alina Espinoza

¹,

W. Ted Brown

⁴,

Clifford Mevs

⁵,

Elaine Marchi

⁴,

Michael Flory

⁶,

Edmund C. Jenkins

⁴,

Milen T. Velinov

⁷

and

Edward V. Quadros

³

¹

Autism Discovery and Treatment Foundation, Phoenix, AZ 85050, USA

²

Department of Psychology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA

³

Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA

⁴

Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA

⁵

Pediatric Health Care, Staten Island, NY 10311, USA

⁶

Research Design and Analysis Core, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA

⁷

Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2025, 26(17), 8293; https://doi.org/10.3390/ijms26178293 (registering DOI)

Submission received: 3 July 2025 / Revised: 19 August 2025 / Accepted: 24 August 2025 / Published: 26 August 2025

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Abstract

Autism Spectrum Disorder (ASD) affects an estimated prevalence of 1 in 31 children but the cause in most cases is unknown. Human and animal studies have linked ASD to Folate Receptor Alpha Autoantibodies (FRAAs). Our previous studies demonstrated that FRAAs are more common, on average, in families with children with ASD. This study reanalyzed data from a previous study which included 82 children diagnosed with ASD, 53 unaffected siblings, 70 mothers, 65 fathers, and 52 typically developing controls who did not have a history of ASD in their family. This study investigates the association of FRAA titers with ASD risk factors and explores the relationship of FRAA titers across generations. Several known risk factors for ASD, including multiplex ASD families, multiple birth pregnancies, and increased maternal and paternal ages at birth, were related to offspring FRAA titers. Multiplex ASD families demonstrated higher FRAA titers. Significant correlation were found between maternal and offspring blocking FRAA titers. FRAA titers increased across generations, although the increase in blocking FRAA titers was only seen in multiplex families. The proband with ASD showed higher blocking but not higher binding, FRAA titers compared to their non-affected siblings. Paternal FRAA titers are associated with several measures of offspring behavior and cognitive development. This research highlights the potential transgenerational transmission of FRAAs and their role in ASD. This supports the notion that heritable non-genetic factors may be important in the etiology of ASD and that FRAAs may demonstrate anticipation (worsening across generations), especially in multiplex families. FRAAs may provide one example of the possibility that susceptibility to autoimmune processes may contribute to disrupted brain development and function in ASD.

Keywords: anticipation; autism spectrum disorder; cerebral folate deficiency; folate receptor alpha; folate receptor alpha autoantibodies; heritability

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MDPI and ACS Style

Frye, R.E.; Cohen, I.L.; Sequeira, J.M.; Hill, Z.; Espinoza, A.; Brown, W.T.; Mevs, C.; Marchi, E.; Flory, M.; Jenkins, E.C.; et al. Transgenerational Effects and Heritability of Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorder. Int. J. Mol. Sci. 2025, 26, 8293. https://doi.org/10.3390/ijms26178293

AMA Style

Frye RE, Cohen IL, Sequeira JM, Hill Z, Espinoza A, Brown WT, Mevs C, Marchi E, Flory M, Jenkins EC, et al. Transgenerational Effects and Heritability of Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorder. International Journal of Molecular Sciences. 2025; 26(17):8293. https://doi.org/10.3390/ijms26178293

Chicago/Turabian Style

Frye, Richard E., Ira L. Cohen, Jeffrey M. Sequeira, Zoe Hill, Alina Espinoza, W. Ted Brown, Clifford Mevs, Elaine Marchi, Michael Flory, Edmund C. Jenkins, and et al. 2025. "Transgenerational Effects and Heritability of Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorder" International Journal of Molecular Sciences 26, no. 17: 8293. https://doi.org/10.3390/ijms26178293

APA Style

Frye, R. E., Cohen, I. L., Sequeira, J. M., Hill, Z., Espinoza, A., Brown, W. T., Mevs, C., Marchi, E., Flory, M., Jenkins, E. C., Velinov, M. T., & Quadros, E. V. (2025). Transgenerational Effects and Heritability of Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorder. International Journal of Molecular Sciences, 26(17), 8293. https://doi.org/10.3390/ijms26178293

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Transgenerational Effects and Heritability of Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorder

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