Over the last five decades, Medical Genetics has evolved from a mostly descriptive discipline into a much more proactive and clinically useful component of healthcare. 

Traditionally medical genetics has been limited by a few factors: laboratories only know to look for mutations that run in families, patients often provide inaccurate or incomplete family histories leading to missed diagnoses, and clinical presentation is complex, and many genetic conditions have overlapping physical features.

With Orchid, these limitations are mitigated: We can screen for more than just known mutations that run in families, we no longer have to rely on patients’ knowledge of their family history, and we no longer even have to wait for an at-risk pregnancy.

Now, obstetric genetics can be profoundly proactive; embryos at risk of genetic forms of developmental and cognitive disabilities are, for the first time, identifiable and avoidable prior to pregnancy. Orchid uses whole genome sequencing preimplantation genetics testing (PGT) to empower patients and their providers to make informed decisions prior to transferring an embryo.

Neurodevelopmental Disorders

A learning, behavioral, or neurological abnormality diagnosis is devastating to families. For the most part, these neurodevelopmental disorders are unknowable before delivery, and are not suspected at birth. They can only be suspected as the child fails to meet developmental milestones that have been established. Evaluation is often subjective and imprecise, accurate diagnoses and causes are rarely known, and therapies can yield varied results. 

Neurodevelopmental disorders encompass a broad range of conditions, primarily falling into three categories: intellectual disability, autism spectrum disorders, and neurologic conditions (e.g., seizure disorders, and disorders of neuromuscular tone). The shared characteristics among neurodevelopmental disorders can complicate accurate identification, and biases in the evaluation process also contribute to diagnostic imprecision.

Genetic Testing for Neurodevelopmental Disorders

Genetic testing for disease is the outcome of decades of studies conducted by geneticists. These studies involve analyzing the DNA of individuals with specific conditions, aiming to identify common genetic "typos" or variations that are absent in unaffected individuals. Through extensive research, geneticists have compiled comprehensive lists of genes and genetic variations associated with various conditions, including Neurodevelopmental Disorders.

Orchid uses this same technology to scan embryos for 200+ known genetic typos that have been known to cause Neurodevelopmental Disorders through decades of research. By employing this approach, parents gain the ability to identify embryos with known genetic forms of neurodevelopmental disorders, empowering them to make informed decisions.

Roughly 30% of individuals with Neurodevelopmental Disorder diagnoses like Intellectual Disabilities, Autism Spectrum Disorder, and Epilepsy have a known genetic cause for their condition. As such, Orchid can make a difference in many families who might be impacted by such a diagnosis 

Reflections on my Patients

Julian was 4 years old when he was referred to my pediatric genetics clinic by a developmental pediatrician. Initially, he had received successful treatment for seizures and had even exceeded some early performance milestones, but in the last six months he had exhibited troublesome developmental regression, losing many of those skills.

Julian’s mother remembered her pregnancy as wonderful and her obstetric and early pediatric providers were initially unconcerned. When I met Julian, he had not yet been evaluated with an IQ or other cognitive tests, and there were no concerns from brain imaging. However, under my supervision, Julian tested positive for a pathogenic mutation in the SYNGAP1 gene. 

At least 40 mutations in the SYNGAP1 gene have been found to cause SYNGAP1-related intellectual disability. In addition to mild-to-moderate intellectual disability, this condition commonly features other neurological problems, including recurrent seizures (epilepsy) and autism spectrum disorder. 

For future families, Orchid can help: The literature suggests that genetics explains a large component (as high as 80%) of Intellectual Disability, and about 30-40% of individuals with intellectual disability will have an identifiable genetic cause. This means that Orchid can help future families identify genetic conditions like SYNGAP1-related intellectual disability for embryos, even before implantation and pregnancy

By far the most common diagnosis for referred patients in my pediatric genetic clinic was autism. Autism spectrum disorder is a condition that appears very early in childhood development, varies in severity, and is characterized by impaired social skills, communication problems, and repetitive behaviors that interfere with an individual’s ability to function in a social, academic, or employment setting. Autism can be a devastating diagnosis. Its suspicion and confirmation is tied to severe parental and familial stress.

Literature suggests that genetic factors are estimated to contribute to 40-80% of autism spectrum disorder, and about 30% of individuals with an autism spectrum disorders will have an identifiable genetic cause. Although we don’t know the specific pathophysiology of autism, we do know that at least 11 genes can be involved: ADNP, CHD2, ANK2, CHD8, ARID1B, DYRK1A, POGZ, SHANK3, and SYNGAP1. Variants or mutations in these genes can be inherited or develop randomly (“de novo”) in the embryo, meaning many children diagnosed with an autism spectrum disorder have no family history of autism.

Lisa was 5 when I met her in my office. Lisa had been diagnosed with autism and had been found to have a mutation in the SHANK3 gene. My patient was Lisa’s pregnant mother and I was seeing her in my high risk obstetric clinic to discuss the chance of this pregnancy inheriting the SHANK3 variant Lisa carries. Because neither of Lisa’s parents carried the same mutation, Lisa’s variant had been de novo and had occurred very early in her development.

For future families, Orchid might have helped: Although all genetic causes of autism spectrum disorders are unknown, Orchid is able to identify many variants in 240 genes known to clearly cause neurodevelopmental disorders including Autism. Screening Lisa’s mother's embryos would have given her peace of mind that her next child would not have the same de novo variant as Lisa. 

Neonatal Seizures Case Study

As an example of another neuro-developmental disorder, consider KCNQ2. KCNQ2 mutations are associated with neonatal-onset developmental and epileptic encephalopathy (NEO-DEE). The family of a child carrying a de novo KCNQ2 mutation was referred to Orchid. Orchid was able to detect a de novo mutation in the child and confirmed the parents were negative. In the IVF lab, Orchid confirmed that the couple’s remaining embryos were negative for the KCNQ2 mutation, meaning their future children would not suffer from the same condition. The couple was also provided reassurance that these embryos were at reduced risk for other disease causing variants in 240 other genes associated with neurodevelopmental disorders. 

For this family, Orchid has helped.

Conclusion

Not all causes of neurodevelopmental disorders are known, and not all are genetic. When it comes to intellectual delay, autism spectrum disorders and epilepsy, we will know more tomorrow than we know today. 

But for the very first time we are able to screen embryos for 240 genes we know to clearly cause NDDs before the pregnancy even begins. We have at our disposal a completely new way of working with patients, clinicians and families. This changes the way that we practice genetics. 

‍