Unlocking the power of PGT-M: A guide to enhanced genetic screening in IVF
In the evolving landscape of assisted reproductive technology, understanding and addressing genetic risks is paramount. This is particularly true for monogenic disorders, which can significantly impact the health of future generations. Preimplantation Genetic Testing for Monogenic Disorders (PGT-M), powered by Next-Generation Sequencing (NGS), offers a powerful tool for IVF labs to enhance their services and help families make informed decisions.
Understanding monogenic disorders
Monogenic disorders are conditions arising from mutations within a single gene. Unlike polygenic disorders, which involve the complex interplay of multiple genes and environmental factors, monogenic disorders follow a more predictable pattern of inheritance. This distinction is crucial for understanding how these disorders are passed down through generations and for developing effective screening strategies. Monogenic disorders are typically inherited in a Mendelian fashion, meaning they follow the principles of inheritance first described by Gregor Mendel. Understanding these patterns – autosomal dominant, autosomal recessive, and sex-linked – is essential for assessing the risk of a child inheriting a particular disorder. In autosomal dominant disorders, only one copy of the mutated gene is needed to cause the disorder, with examples including Huntington's disease and certain forms of familial hypercholesterolemia. Autosomal recessive disorders require two copies of the mutated gene for the disorder to manifest, such as in the cases of cystic fibrosis and sickle cell anemia. Finally, sex-linked disorders are those where the mutated gene resides on a sex chromosome (X or Y); hemophilia and Duchenne muscular dystrophy are examples of X-linked disorders.
Commonly screened monogenic disorders
PGT-M allows for the screening of a wide range of monogenic disorders, providing prospective parents with valuable insights into the genetic health of their embryos. The specific genes targeted often depend on family history, ethnicity, and the specific offering of the testing laboratory. Here we will focus on a selection of commonly screened genes and their associated disorders to illustrate the power of PGT-M.
BRCA1 and BRCA2
Mutations in the BRCA1 and BRCA2 genes are most famously associated with an increased risk of hereditary breast and ovarian cancers. These genes play a crucial role in DNA repair, and certain mutations can significantly elevate the lifetime risk of developing these cancers. Harmful BRCA1 and BRCA2 variants occur in about 1 in 400 individuals in the general population, but their prevalence can be higher in certain populations. For example, founder mutations are more common in individuals of Ashkenazi Jewish descent, with about a 1 in 40 chance of carrying one of three specific mutations. Founder mutations are also known to exist in those of Dutch, Swedish, and Norwegian ancestry.
CFTR
As previously mentioned, mutations in the CFTR gene cause cystic fibrosis, an autosomal recessive disorder affecting the lungs, pancreas, and other organs. Cystic fibrosis affects about 1 in 2,500 to 3,500 white newborns and is most common in Caucasians of Northern European ancestry. It is less common in other ethnicities, occurring in about 1 in 17,000 African Americans and 1 in 31,000 Asian Americans.
DMD
The DMD gene provides instructions for making dystrophin, a protein essential for muscle function. Mutations in this gene cause Duchenne muscular dystrophy (DMD), a severe X-linked recessive disorder characterized by progressive muscle weakness and degeneration. DMD affects approximately 1 in 3,500 to 5,000 male births worldwide and occurs across all races and ethnicities. Interestingly, some studies suggest a slightly higher incidence in Hispanic populations compared to white or black populations.
HBB
The HBB gene is critical for producing a component of hemoglobin. Mutations in this gene can lead to beta-thalassemia and sickle cell anemia, both autosomal recessive disorders. Sickle cell disease affects approximately 100,000 Americans and is most common in people of African descent, affecting about 1 in 365 African American births. Beta-thalassemia is more prevalent in people of Mediterranean, Asian, and African descent.
F8
The F8 gene provides instructions for making coagulation factor VIII, a protein essential for blood clotting. Mutations in this gene cause hemophilia A, an X-linked recessive bleeding disorder. Hemophilia A is the most common type of hemophilia, affecting about 1 in 5,000 male births worldwide, and occurs across all races and ethnicities.
FMR1
The FMR1 gene is involved in cognitive development. Expansions of a CGG repeat within this gene cause Fragile X syndrome, an X-linked dominant disorder that is a common cause of inherited intellectual disability. Fragile X syndrome affects about 1 in 4,000 to 7,000 males and 1 in 8,000 to 11,000 females and is found worldwide across all races and ethnicities.
GJB2
The GJB2 gene encodes connexin 26, a protein that forms gap junctions, allowing for cell-to-cell communication. Mutations in GJB2 are a major cause of autosomal recessive non-syndromic hearing loss. GJB2-related hearing loss is one of the most common genetic causes of hearing loss, with a carrier frequency of up to 1 in 33 in some populations. The prevalence of GJB2 mutations varies among different populations, with certain mutations being more common in individuals of European and Ashkenazi Jewish descent.
Advances in NGS technology
NGS technology has revolutionized genetic testing, enabling faster and more comprehensive analysis of an individual's genetic makeup. In the context of PGT-M, NGS allows for the simultaneous screening of multiple genes, providing a more complete picture of an embryo's genetic health compared to older, more limited sequencing methods.
Ongoing advancements in NGS are pushing the boundaries of what's possible in genetic screening. We are moving beyond simply identifying known mutations, towards a more holistic understanding of the genome. For instance, researchers are exploring the use of polygenic risk scores (PRS) in conjunction with PGT-M to provide a more comprehensive assessment of an embryo's genetic predisposition to complex diseases like heart disease or diabetes, going beyond single-gene disorders. Furthermore, advancements in long-read sequencing technologies may soon enable the detection of structural variants and repeat expansions, which are currently challenging to identify with standard NGS methods. We are also seeing advancements in detecting mitochondrial DNA disorders, which could eventually be detected using PGT-M. These types of advances will expand the scope of PGT-M, offering even greater insights into an embryo's future health. Moreover, as the cost of sequencing continues to decrease, PGT-M is likely to become more accessible to a wider range of individuals seeking assisted reproductive technologies. The development of non-invasive preimplantation genetic testing (niPGT), which analyzes DNA found in the embryo's culture media, promises to further simplify the process, potentially eliminating the need for embryo biopsy.
Conclusion
Understanding monogenic disorders and the power of PGT-M is essential for any IVF lab striving to provide the best possible care. By embracing these advances in genetic testing, labs can empower families with knowledge, helping them navigate the complexities of family planning and ultimately improving the health and well-being of future generations. The future of reproductive medicine is undoubtedly intertwined with the continued evolution of genetic testing and personalized medicine, and PGT-M is at the forefront of this exciting journey.
References
- Cost effectiveness of in vitro fertilization and preimplantation genetic testing to prevent transmission of BRCA1/2 mutations. Doi: 10.1093/humrep/dez203
- Cystic fibrosis, Duchenne muscular dystrophy and preimplantation genetic diagnosis. Doi: 10.1093/humupd/2.6.531
- Preconception carrier screening and prenatal diagnosis in thalassemia and hemoglobinopathies: challenges and future perspectives. Doi: 10.1080/14737159.2017.1285701
- Four Decades of Carrier Detection and Prenatal Diagnosis in Hemophilia A: Historical Overview, State of the Art and Future Directions. Doi: 10.3390/ijms241411846
- Impact of FMR1 Pre-Mutation Status on Blastocyst Development in Patients Undergoing Pre-Implantation Genetic Diagnosis. Doi: 10.1159/000455849 6.
- Preimplantation genetic diagnosis (PGD) for nonsyndromic deafness by polar body and blastomere biopsy. Doi: 10.1007/s10815-009-9335-5
- ESHRE PGT Consortium good practice recommendations for the detection of monogenic disorders. Doi: 10.1093/hropen/hoaa018
