Pre-Implantation Genetic Testing for Birth Defects

Pre-Implantation Genetic Testing for Birth Defects

Written by Dr. Nathan Slotnick, MD, PhD

Dr. Slotnick is a board certified Medical Geneticist and High Risk Obstetrician with over 40 years of practice. Throughout his career, Dr. Slotnick has dedicated himself to academic genomic and perinatal medicine with an expertise in research, teaching and programmatic development, consistently seeking ways to harness emerging technologies for the advancement of medicine, equity in healthcare and the enhancement of patient care.

Over the past five decades, Medical Genetics has transformed from primarily a descriptive field into a proactive and clinically valuable component of healthcare.

The discussions between medical genetic/perinatal providers and expectant families around birth defects can be among the most intricate and emotionally challenging. These conversations are delicate, and involve helping families come to terms with the unexpected loss of what they had, up until that point, envisioned as a typical and joyous pregnancy journey.

Significant advancements have been made in prenatal care and fetal imaging in the past two decades. Ultrasound has become a standard practice throughout pregnancy. However, similar to other clinical imaging techniques, ultrasound remains primarily descriptive in nature.

When abnormalities are detected, lives are profoundly impacted and families experience immense stress. I personally experienced this throughout my 30-year practice. Obstetric sonography identifies fetuses that may be at risk of, or already are displaying malformations. By analyzing ultrasound images in conjunction with daily history and genetic screens, healthcare providers such as myself strive to offer precise diagnoses and accurate prognoses. In certain cases, therapeutic interventions may also be initiated based on the information obtained. However, there is no way to reduce the risk of malformation prior to pregnancy.

Orchid intends to change this

When evaluated in the nursery, 3-5% of all newborns have at least one birth defect. There are thousands of birth defects that have been described over the years as all tissues and organs can be affected, from brain to heart to limbs. Many can be obstetrically visualized, some much better than  others. Many have only subtle visible phenotypes and their identification is difficult. Many are missed.

The majority of fetal malformations are typically not isolated. Abdomen, heart, spine and genital abnormalities run together and are often tied to learning or behavioral problems that are not suspected before birth. 

Many require life-saving action immediately following delivery, and unfortunately many are fatal.  

At Orchid, we can look for more than just known mutations that run in families. We no longer even need to wait for a pregnancy to begin our work.

For the first time, birth defect genetics can be profoundly proactive. Orchid’s whole genome sequencing for embryos can screen for and identify embryos at risk for genetic birth defects, empowering patients to make informed decisions prior to transferring an embryo. All of this before a pregnancy even begins.

A story of multiple malformations 

A physician colleague reached out to discuss a concerning situation involving Tammy, a long-term patient who was pregnant with her fourth child. All her previous pregnancies had been smooth, and her children were healthy.  At thirty weeks into her pregnancy, her physician was worried about the fetus's small size and had difficulty in visualizing the heart.

When evaluating suspected malformations, it is crucial to comprehensively examine the fetal anatomy using sonography, considering every detail from head to toe. The provider's expertise plays a critical role in identifying and confirming patterns and types of abnormalities.

Tammy was understandably distressed when I met her. As I conducted the examination, I discovered a malformed heart, as well as limb abnormalities and an extra finger on each hand. While numerous conditions share similar features, I had a suspicion. Subsequent testing confirmed mutations in both EVC genes, indicating the presence of the rare autosomal recessive Ellis-van Creveld syndrome. 

Ellis-van Creveld syndrome is one of the 900+ conditions screened for on Orchid’s birth defect gene panel. Orchid can help families like Tammy's

Lethal Skeletal Malformations 

Gillian knew that a referral to see a perinatologist was a problem. She was in her 4th pregnancy and had 3 healthy children at home. She and her partner were completely healthy and there were no concerns about her family history (or her partner’s) that I could elicit. 

Her pregnancy had been normal so far, but she felt smaller than during her three prior. She also felt much less movement. Her doctor  had mentioned that the bones in the fetal limbs were “pretty short.” Ultrasound showed that the limbs were tiny because the bones were very short and poorly formed. All of the fetal long bones measured a small fraction of what they should have. The fetal ribs and spine were poorly formed. The brain was abnormal and the skull was shaped like a clover leaf. Most pertinently, the chest was terribly small.  

It became clear that this fetus had a lethal skeletal dysplasia, thanatophoric dysplasia. It was caused by a pathogenic mutation in the FGFR3 gene which is involved in bone formation. It is lethal, not because of the bony abnormalities per se, but because the chest develops so poorly that at delivery the fetus can not breathe. Due to its fatality, thanatophoric dysplasia is not inherited from parents, but rather occurs due to a random mutation (de novo) in embryos. Orchid can screen for mutations in FGFR3, along with hundreds of others that cause similarly catastrophic conditions.


While genetic testing before pregnancy has made significant advancements in identifying parents whose child may have an increased chance of a birth defect, there are still limited risk mitigation options before conception. Typically, detection and evaluation during pregnancy are the primary methods used to identify and address potential birth defects.

In cases where patients are aware of their family genetic history and know the specific gene variant they wish to prevent their child from inheriting, Preimplantation Genetic Testing for Monogenic Disorders (PGT-M) is possible. For birth defects in particular, this approach is less helpful as a vast majority of problematic mutations occur randomly (de novo). Testing parents would not be helpful in these cases.

Orchid’s embryo screen does not face these limitations. By reading an embryo’s entire genome, we can identify variants in hundreds of genes that are known to directly cause birth defects, regardless of family history, and even if the mutation happened randomly. All of this, even before pregnancy begins.

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