Can a pathogenic FLT4 (fibroblast growth factor receptor-like 4) gene mutation, which is autosomal dominant, be carried by one or both parents, given an 18-week fetus with a boot-shaped heart and truncus arteriosus, and what is the risk for future pregnancies?

From the Guidelines

Yes, it is possible that one of the parents is a carrier of the pathogenic FLT4 gene mutation, which is associated with autosomal dominant inheritance. Since the condition is autosomal dominant, only one parent needs to carry the mutation to potentially pass it to offspring, with each pregnancy having a 50% chance of inheriting the mutation. Future pregnancies would be at risk for the same condition. The FLT4 gene (also known as VEGFR3) is involved in cardiovascular development, and mutations can lead to congenital heart defects like truncus arteriosus and boot-shaped heart. These cardiac abnormalities, while sometimes seen in DiGeorge syndrome, can occur independently due to FLT4 mutations.

Key Considerations

• Genetic counseling is strongly recommended for the parents, and prenatal genetic testing should be offered in future pregnancies 1.
• Both parents should undergo genetic testing to identify which parent carries the mutation, as this information is crucial for family planning.
• If the mutation is de novo (newly occurring in the fetus), the recurrence risk would be lower but still present due to the possibility of germline mosaicism in a parent.
• The risk of transmission of disease can be explained through prenatal genetic counseling, and potential reproductive options can be discussed, including in vitro fertilization with preimplantation genetic diagnosis, prenatal genetic screening, and postnatal genetic testing 1.

Implications for Future Pregnancies

• Each pregnancy will have a 50% chance of inheriting the mutation if one parent is a carrier.
• Prenatal genetic testing can help identify affected fetuses, allowing for informed decision-making about the pregnancy.
• Genetic testing after careful counseling has the rationale of identifying at-risk asymptomatic or disease-free relatives and to guide clinical surveillance for disease onset, thereby enhancing preventive and treatment interventions 1.

Importance of Genetic Testing and Counseling

• Genetic testing may be useful in cardiomyopathies and channelopathies, such as long QT syndromes, when other family members are affected, or when the patient has dysmorphic features, developmental delay/mental retardation, or when other non-cardiac congenital abnormalities are present 1.
• The inheritance pattern differs among the diseases, and therefore genetic counseling by a geneticist is highly recommended for patients and their family members.

From the Research

Genetic Implications of FLT4 Gene Mutation

The presence of a pathogenic FLT4 gene mutation in an 18-week fetus, characterized by a boot-shaped heart with truncus arteriosus, suggests a potential genetic link to congenital heart defects (CHDs) 2, 3. The fact that the fetus tested negative for DiGeorge syndrome indicates that the cardiac anomalies are likely related to the FLT4 gene mutation.

Carrier Status of Parents

Given that the FLT4 gene mutation is autosomal dominant, it is possible that one or both parents are carriers of the mutation 3. The mutation can be inherited from either parent, and the likelihood of transmission to offspring depends on the genotype of the parents.

Impact on Future Pregnancies

The presence of a pathogenic FLT4 gene mutation in the fetus increases the risk of recurrence in future pregnancies, particularly if one or both parents are carriers 2, 3. The risk of transmission and the likelihood of expressing the condition in future offspring depend on the genotype of the parents and the specific mutation involved.

Key Findings

• A novel stop-gain pathogenic variant in FLT4 has been associated with congenital heart defects, including truncus arteriosus 2.
• Rare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF) and Milroy disease, which can manifest as distinct phenotypes due to pleiotropic molecular mechanisms 3.
• A novel missense mutation in FLT4 can cause autosomal recessive hereditary lymphedema, highlighting the genetic heterogeneity of the condition 4.

Considerations for Genetic Counseling

The identification of a pathogenic FLT4 gene mutation in the fetus has significant implications for genetic counseling and family planning. Parents should be informed about the risks of recurrence and the availability of genetic testing to determine their carrier status and the genotype of future offspring.