PGT-M Offers a Strategy for Epileptic Women with Monogenic Disorders Caused by FLNA Mutation

Technical Summary: PGT-M Strategy for Epileptic Women with FLNA Mutations

Problem Statement
Mutations in the Filamin A (FLNA) gene, located on the X chromosome (Xq28), cause a spectrum of multisystem disorders, most notably periventricular nodular heterotopia (PVNH), a primary cause of epilepsy. Women of childbearing age with FLNA-related epilepsy face significant reproductive challenges, including a high risk of vertical transmission of the pathogenic variant, pregnancy complications, and adverse fetal outcomes. Traditional prenatal diagnosis (e.g., amniocentesis) is limited by gestational age constraints, procedural invasiveness, and the psychological trauma associated with terminating an affected pregnancy. Furthermore, while FLNA mutations are known to cause severe phenotypes in males (often lethal prenatally or in early infancy) and variable, often symptomatic phenotypes in females, there is a lack of documented strategies to prevent vertical transmission specifically for FLNA-related epilepsy.

Methodology
The study presents a case report of a 32-year-old Chinese woman with a 15-year history of epilepsy and a confirmed heterozygous FLNA mutation (NM_001456.3:c.506dup, p.Gln170Alafs*43). The patient had a history of an adverse pregnancy (fetal termination at 14 weeks due to cystic hygroma and cardiac malformations) and sought assisted reproductive technology.

The methodology involved a multidisciplinary approach (neurology, obstetrics, and reproductive medicine) to evaluate the patient for Preimplantation Genetic Testing for Monogenic Disorders (PGT-M). The protocol included:

1. Genetic Verification: Confirmation of the FLNA mutation and haplotype analysis to determine inheritance (suggesting paternal mosaicism or a de novo germline mutation).
2. In Vitro Fertilization (IVF): Ovarian stimulation and embryo culture.
3. PGT-M and PGT-A: Biopsy of embryos to screen for the specific FLNA pathogenic variant (c.506dup) and aneuploidy (PGT-A).
4. Embryo Selection: Transfer of only euploid embryos verified as free of the FLNA mutation.
5. Prenatal and Postnatal Validation: Prenatal diagnosis of transferred embryos and postnatal clinical/MRI assessment of the resulting children.

Additionally, the authors conducted a literature review (searching PubMed up to March 16, 2025) to characterize the mutational spectrum of FLNA and compare the identified variant with existing data.

Key Results

• Clinical Outcome: The patient successfully underwent two cycles of IVF with PGT-M (in 2022 and 2024). Two healthy female infants were born via cesarean section. Both children are currently seizure-free with normal growth and development. Postnatal MRI of the second child confirmed the absence of PVNH.
• Genetic Findings: The study identified a novel FLNA mutation (c.506dup), expanding the known mutational spectrum of the gene. No identical mutation locus was found in the 67 retrieved studies covering FLNA-associated PVNH and epilepsy.
• PGT-M Efficiency: Out of 8 biopsied embryos, 4 were identified as euploid and free of the FLNA mutation (2 female, 2 male), while 4 were either affected by the mutation or aneuploid. The transfer of unaffected embryos resulted in successful live births.
• Literature Synthesis: The review confirmed that FLNA-related PVNH has nearly complete penetrance in postnatal survivors. While male carriers typically face severe, often lethal phenotypes, female carriers exhibit a heterogeneous spectrum (60–70% develop symptoms like epilepsy). The study notes that approximately 90% of PVNH patients develop drug-resistant seizures, and surgical resection is often precluded by the deep, bilateral nature of the lesions.

Significance and Claims
The paper claims that this is the first reported case of a woman with FLNA-related epilepsy successfully delivering healthy offspring via PGT-M. The authors argue that PGT-M offers a safe, effective, and non-invasive preconception strategy to mitigate the high reproductive risks associated with FLNA mutations.

Key claims regarding the study's significance include:

• Prevention of Vertical Transmission: PGT-M effectively prevents the transmission of pathogenic FLNA variants, avoiding the need for invasive prenatal diagnosis and the potential termination of affected pregnancies.
• Clinical Utility: For patients with inoperable, drug-resistant epilepsy caused by PVNH, PGT-M is presented as a superior alternative to post-onset management, which often yields poor outcomes.
• Reproductive Counseling: The authors propose that PGT-M should be considered a routine preconception intervention for women with pathogenic FLNA mutations, provided there is a clear genetic diagnosis, a defined inheritance pattern, and a favorable benefit-risk balance.
• Novelty: The identification of the c.506dup variant contributes to the genetic database of FLNA disorders, aiding future diagnostic accuracy.

The study concludes that while ethical and economic considerations exist, PGT-M provides a reliable clinical strategy for genetic counseling and reproductive management, significantly improving clinical outcomes for families affected by FLNA-related epilepsy.