Precision Medicine Online and My Gene Counsel have partnered since 2019 on the "Genetic Testing Challenges" series to highlight real-world issues medical professionals are encountering as genetic tests are increasingly used in patient care. Healthcare providers and genetics experts share anonymized case reports with My Gene Counsel, and based on the submitted details, Precision Medicine Online writes features that describe the case history, difficulties encountered by professionals managing the cases, and how they responded to challenges or errors. The features also include a discussion with My Gene Counsel genetic counseling experts on better approaches for addressing similar challenges in the future. In publishing this series, our aim is to educate and foster discussion among professionals interested in improving precision medicine access. If you would like to submit a case report, please email [email protected].
What happened?
A 29-year-old Ashkenazi Jewish woman went to her Ob/Gyn for pre-pregnancy carrier screening and learned that she carried one pathogenic variant in the HEXA gene associated with Tay-Sachs disease and one in the SMN1 gene associated with spinal muscular atrophy (SMA). Both are autosomal recessive disorders, meaning that a person must inherit two mutated copies of the gene, one from the mother and one from the father, to have the disorder. Since her carrier status for Tay-Sachs and SMA could impact a future pregnancy, the Ob/Gyn recommended that her husband, who was also Ashkenazi Jewish, undergo carrier screening through his primary care provider to better understand their risks.
The husband's doctor ordered testing to check his hexosaminidase A levels, the enzyme encoded by the HEXA gene that is low or absent in Tay-Sachs patients. The test showed abnormal enzyme levels, indicating the husband likely also carried a pathogenic variant in HEXA associated with Tay-Sachs. In the most common, infantile form of this neurodegenerative disorder, patients experience developmental delay, vision loss, and seizures starting at 6 months of age. The symptoms then worsen, and the condition is typically fatal by age 5.
How was this case solved?
The husband's doctor had a virtual consultation with genetics experts to discuss the case, and they advised full sequencing of the husband's HEXA gene. The doctor ordered a genetic test, and it didn't detect any pathogenic variants linked to Tay-Sachs in the husband. Reassured, the couple proceeded with their plans to have a child.
The woman eventually gave birth to a baby girl. However, by 1 year of age, the family and doctors noted that the baby was not progressing as she should have been. After many medical consultations, the child was diagnosed with Tay-Sachs at 15 months. She died when she was just 2 1/2 years old.
A review of the medical records showed that the husband's doctor hadn't ordered full sequencing for the HEXA gene, as recommended by the genetics experts. Instead, he mistakenly ordered a panel that only tested for the most common pathogenic variants associated with Tay-Sachs. After his daughter was diagnosed with Tay-Sachs, the father had the full sequencing test performed and found he indeed carried a different pathogenic variant in HEXA.
Why is this case concerning?
This case is concerning because this Ashkenazi Jewish couple was never referred for genetic counseling: not after the woman was found to carry a pathogenic variant in HEXA, not after her husband had an abnormal hexosaminidase A enzyme test, and not to review the results in this high-risk situation to ensure that appropriate tests had been ordered and interpreted correctly.
More than 200 pathogenic variants are known to cause Tay-Sachs disease, most commonly in people of Ashkenazi Jewish ancestry. Most of the variants associated with the severe, infantile form of the disorder render the hexosaminidase A enzyme nonfunctional or significantly reduce its activity. Other variants that reduce the activity of the enzyme, but maintain some functionality, are associated with less severe, rarer forms of Tay-Sachs that manifest later in life.
When this Ashkenazi Jewish woman's preconception carrier screening test found a pathogenic variant in HEXA, this should have already been flagged as a high-risk case, said Ellen Matloff, a certified genetic counselor and president and CEO of the digital health firm My Gene Counsel. "But when the enzyme test for the husband, who is also Ashkenazi Jewish, came back abnormal, at that point, this case should have gone from a high-risk situation to flashing red lights, because now we have the wife who is a carrier and the husband is most likely a carrier," she said.
It is further concerning that although the husband's doctor was advised to order full sequencing of HEXA, the physician, when ordering the test, mistakenly chose a panel only designed to pick up the most common variants. And finally, when the genetic test came back negative for any pathogenic variants, the doctor didn't note the discrepancy with the earlier abnormal enzyme test. "The physician should have picked up that something wasn't right here," Matloff said. "Why was the enzyme test abnormal and the genetic testing negative?"
What could have been done differently?
At multiple points during this couple's preconception assessments, there were opportunities to bring in a genetics expert to counsel them about the risk of Tay-Sachs to any resulting fetus and discuss appropriate testing, but this wasn't done. If Matloff were one of the genetics experts who counseled the husband's doctor, upon seeing that the wife carried a pathogenic variant in HEXA and the husband had an abnormal enzyme test, she would have asked to counsel the couple directly.
"I would have said, 'I'll see the patients. But if that's not possible, since this is such a high-risk case, when you get the husband's full sequencing results, send them to me for review,'" Matloff said. "Keep in mind, this is not a pregnant couple. This is all pre-pregnancy, so they had time to do this exactly the right way."
As genetic testing is increasingly implemented in patient care, it's not practical from a healthcare resource standpoint to provide every patient undergoing genetic assessment with pre- and post-test counseling. Still, it's high time, in Matloff's view, that healthcare practices invest in better tools and put processes in place for ensuring that both patients and clinicians get the genetic counseling information they need both pre- and post-testing. As the founder of My Gene Counsel, a firm that provides digital tools that scale accurate genetic counseling information, Matloff believes greater use of these types of tools can reduce errors like the ones in this case. But other process or personnel changes at medical centers, or even programming decision support alerts within the electronic medical record system aimed at ensuring that the patients who should receive guideline-concordant genetic testing and counseling are getting it, could help avoid these types of mistakes, she noted.
The couple in this case proceeded with preconception screening, as is recommended for all couples considering a pregnancy. "In the world of genetics, this is a fairly straightforward case. But this situation highlights that a case that is straightforward for a genetic counselor is not necessarily straightforward for the average clinician. Clinicians are busy, stressed, and they aren't used to ordering genetic tests. We should not ask them to be genetics experts," Matloff stressed. "This couple did exactly the right things at the right time. That's part of the tragedy here."
Once it was known the woman carried a variant in HEXA and the husband's hexosaminidase A enzyme wasn't functioning properly, "this tragedy would have been avoided if someone reviewed the husband's test order or results to ensure it was correct."