Family Planning and Parental Genetic Disease Risks
First-time parents often ponder numerous questions about their future new addition to the family. It is very common to wonder about the health and wellbeing of the baby and if they will develop into a healthy child. Although some families prefer to be surprised by the sex of their baby, they do not want any surprises regarding their baby’s health. Many now are seeking ways to have clues and information to plan for the future even before conception.
Genetic testing before conception provides some valuable information for soon-to-be first-time parents. Those who are planning to expand their family often prefer to know if they carry a gene for a disease that can be passed to their offspring. Some prefer to forgo having children if the risk of passing an incurable disease is high. For example, those who carry the abnormal gene for Huntington’s disease may not have symptoms for years and would not know if they carry this gene without genetic testing. If a person is found to carry the gene, they can make some informed decisions regarding their reproductive choices. This issue can be somewhat complicated since testing positive in one parent, or even both, does not mean there is a 100% chance that the baby will have the genetic disorder. However, some decide that the consequences may be too great to risk passing on a disorder to their offspring.
Common genetic conditions or diseases that future first-time parents can be concerned about include life-threatening conditions such as cystic fibrosis and fragile X syndrome. Cystic fibrosis, which occurs more in white northern European populations, causes gastrointestinal complications and lung damage. Fragile X syndrome causes birth defects including neurological conditions. Sickle cell disease is another genetic disorder and is more common in those of African descent.
Some people may not have a particular concern regarding passing specific genetic abnormalities to their offspring, or they may have an unplanned pregnancy that removes the possibility of preconception testing for the particular pregnancy. However, they may still be concerned about the possibilities of birth defects. Prenatal detection of birth defects is performed to help future parents know whether the fetus may be at high or low risk of developing a birth defect. Although prenatal testing to determine the risk of abnormal development may provide relief when the test results are negative, positive results may add anxiety and confusion regarding any decisions based on those results. Therefore, the choice to test is an intimately personal one that should be accompanied by counseling and sufficient analysis for sound decision making.
Non-Invasive Prenatal Testing
Technologies continue to develop to screen and diagnose conditions in the developing fetus. These developments not only address the accuracy and predictive value of screening methods but also minimizing the risk of harm to the developing offspring. Conventional testing methods during the first trimester have been associated with concerns of fetal loss from the testing.
Noninvasive prenatal testing (NIPT) provides expecting parents valuable and actionable information while greatly reducing the risk of pregnancy loss caused by invasive screening and diagnostic approaches. Techniques have already been developed to provide accurate screening and diagnostic data. The use of next-generation sequencing (NGS) in clinical medicine has opened the door for enhanced utility of NIPT.
Prenatal Testing Advances by Next-Generation Sequencing
Next-generation sequencing is massively parallel DNA sequencing technology that has transformed the field of personalized medicine due to the speed of obtaining genomic data results at a significantly reduced price compared to conventional sequencing technology. The use of NGS in clinical medicine is ever increasing and includes uses such as determining an individual’s disease risk factors and to diagnose a number of diseases including various cancers. Thus far, NGS efforts have facilitated determining the best treatment plans customized to individual patients, finding the underlying basis of conditions that are difficult to diagnose, and diagnosing genetic disorders.
Up to 20% of the total cell-free DNA present in maternal plasma is cell-free fetal DNA and has been exploited to detect fetal aneuploidies using NGS. A number of clinical studies using NGS for fetal aneuploidy detection have shown detection rates of over 90% while the false positive rates remain below 1% 1, 2. Jensen et al 3 collected maternal blood to perform massively parallel sequencing (MPS) on extracted DNA. Their goal was to apply MPS assay enhancements (such as higher sample multiplexing during sequencing) and improved bioinformatics tools to improve the clinical utility of the approach. They were able to improve the already high sensitivity and specificity of the non-invasive NGS approach for fetal aneuploidy detection.
An international clinical validation study reported by Palomaki et al4 analyzed data from tests based on NGS in Down syndrome and matched euploid pregnancies. They found that the Down syndrome detection rate was over 98% with a false positive rate of under 0.5%. These studies indicate the potential utility of this approach in routine clinical screening.
Beta-thalassemia is an inherited blood disorder that causes a reduction in the production of hemoglobin. Papasavva et al5 analyzed single-nucleotide polymorphisms (SNPs) using NGS on maternal blood samples from individuals at risk of carrying an offspring with β -thalassemia. Their results indicate that the NGS analysis of SNPs is more rapid and cost effective than whole genome amplification for the detection of β -thalassemia.
Xiong et al6 determined the accuracy of NGS in detecting paternal β-thalassemia mutations. They analyzed cell-free fetal DNA from maternal blood plasma extracted from those who were from families where both parents were carriers of β-thalassemia mutations. They showed that it was possible to detect paternal β-thalassemia mutations with high sensitivity and specificity using NGS and that the need for invasive testing decreased to only 50% of the tested pregnancies.
Next-generation sequencing is rapidly becoming a powerful NIPT approach to detect a number of inherited diseases. Its utility for first-time parents includes preconception and postnatal testing that allows informed reproductive planning decisions. Further, using NIPT significantly lowers the risk of pregnancy loss that is possible with the long-used invasive procedures.
However, the issue of preconception and prenatal genetic testing is not without significant ethical and legal challenges. The societal concerns for health status discrimination are more apparent with the availability of genetic data. The benefits of genetic testing for very severe genetic diseases are much clearer since the information acquired allows future parents to make decisions about their reproductive future. However, there is growing societal concern that the information provided by use of the technologies can be used for reasons that are not necessarily in the best interest of future offspring. Further, the value of the information and impact on the individuals being testing must be taken into consideration, for this reason, expert counseling is recommended.
- Ehrich M, Deciu C, Zwiefelhofer T, Tynan JA, Cagasan L, et al. (2011) Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol 204: 205 e1–11.
- Palomaki GE, Deciu C, Kloza EM, Lambert-Messerlian GM, Haddow JE, et al. (2012) DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med 14: 296–305.
- Jensen TJ, Zwiefelhofer T, Tim RC, Džakula Ž, Kim SK, et al. (2013) High-throughput massively parallel sequencing for fetal aneuploidy detection from maternal plasma. PLoS One 8(3):e57381.
- Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, et al. (2011) DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 13(11):913-20.
- Papasavva et al (5) analyzed single-nucleotide polymorphisms (SNPs) using NGS on maternal blood samples from individuals at risk of carrying an offspring with β -thalassemia. Their results indicated that the NGS analysis of SNPs was more rapid and cost effective than cost-effective than whole genome amplification for the detection of β -thalassemia. Eur J Hum Genet. 21(12):1403-10.
- Xiong L, Barrett AN, Hua R, Tan TZ, Ho SS, et al. (2015) Non-invasive prenatal diagnostic testing for β-thalassemia using cell-free fetal DNA and next generation sequencing. Prenat Diagn 35(3):258-65.