Carrier screening tests and whole exome sequencing for birth defects

Renyi Hua, a specialist in maternal-fetal medicine and prenatal diagnostics at the International Peace Maternity and Children’s Hospital in Shanghai, China, discusses her experience with whole exome sequencing and carrier screening tests in this NewsMedical interview.

What services are provided and what kinds of patients are treated at the International Peace Maternity and Children’s Hospital?
Despite the fact that we specialize in prenatal care, we also treat adult patients and assist with prenatal diagnostics. We first recommend karyotyping with or without chromosomal microarray analysis to patients who have undiagnosed or unclear dysplasia or dysmorphism. Depending on their phenotype, whole exome sequencing or other procedures may be recommended if no anomalies are discovered.
Because our findings will aid them in their goals for conception, the Assisted Reproductive team refers quite a few patients to us.

Pregnant women who satisfy our criteria may be provided an invasive prenatal diagnosis for specific prenatal cases. These criteria may include advanced maternal age, hereditary disease history in the family, unusual childbearing patterns, parents who have chromosome abnormalities, high risk, structural ultrasound findings of anomalies, abnormal prenatal screening test results, or other circumstances that support the need for invasive testing.

Can you explain the procedure used to decide which tests must be performed on patients?
The nuchal fold would first be scanned at roughly 11 to 13 weeks plus six days. NIPT or Down’s screening will be provided if the results are normal and the woman does not meet the requirements for invasive procedures. If the mother satisfies the requirements or if there is a thicker nuchal fold, chorionic villus sampling (CVS) or an appointment for amniocentesis will be scheduled.

At 22 to 24 weeks, an abnormality ultrasound scan will be performed as the subsequent ultrasound. An amniocentesis for the karyotype and a chromosomal microarray study will be recommended if there is a significant malformation or multi-system abnormalities (CMA).

Trio-whole exome sequencing (Trio-WES) will be made available if the results are normal. When the abnormalities appear late in an ultrasound, there are some exceptional cases. After 26 weeks, we will talk with the parents about whether it is morally acceptable to run CMA and Trio-WES concurrently.

What standards did you use when you first started using whole exome sequencing (WES)?
Our WES was launched in 2019. We had more than 600 samples in total in 2020, of which more than 100 were Trio-WES and nearly half were singletons. We had a significant increase in 2021, with more than 1,000 samples. There were almost 200 singletons and roughly 300 Trio-WES among them. Trio-WES are relatively common because we altered our procedures that year to include parents in cases involving unborn children.

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Up until September of this year, we had more than 700 samples, of which more than 200 were Trio-WES and less than 100 were singletons. The overall success rate was under 20%. This year, a thickened nuchal fold or hidrocystoma, a cardiovascular abnormality, and several anomalies met our criteria for Trio-WES.

How do carrier screening exams work at your institution?
We have been employing a panel of 155 inherited genetic disorders that span various organ systems and body parts. Then, we proceed according to the procedure we employ in the clinic: we advise women who are not pregnant or who are pregnant but are less than 14 weeks along to take the test first and by themselves.

If the mother’s test is positive, we usually simply test the partner. We advise that both parents do the tests if the lady is more than 14 weeks pregnant in order to expedite any potential prenatal diagnoses.

Would you mind sharing a few of the cases from this year and how these services influenced medical choices?
This year, we have almost 3,000 cases. At least one harmful or likely pathogenic mutation was present in nearly half of the candidates. The same gene was mutated in several couples. A few of them choose to have natural conceptions and subsequent prenatal diagnoses. Preimplantation genetic testing was chosen by others (PGT).

In one instance, a 32-year-old woman who was carrying a 12-week pregnancy underwent a carrier screening test. While the partner’s test came out negative, the woman was found to have a mutation in the SMN1 and EDA genes. We suggested an amniocentesis to check for the EDA gene and chromosome abnormalities.
For her subsequent pregnancies, we advised either a PGT or a natural conception with the prenatal diagnosis because the outcome was a homozygous male.

Another incident involved a 28-year-old Korean national who was 13 weeks pregnant. Her carrier screening test results revealed Wilson’s disease-causing mutation in both the MMAB and ATP7B genes. Her spouse had a Korean nationality and had the ATP7B gene mutation.

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We suggested an amniocentesis for chromosomal abnormalities and an ATP7B gene test for her. Fortunately, the heterozygous fetus only acquired the mutation from her mother, and the mother is continuing to grow.

The third case involved a 35-year-old lady with an unusual history of childbirth. Due to fetal abnormality, she underwent an abortion in 2015. She did not preserve any samples from the infant or undergo any genetic testing. The woman’s scan at 13 weeks of her subsequent pregnancy revealed punctiform limbs and an unnatural nuchal fold. She received a CMA and Trio-WES from us.

The phenotypic of this infant fits what we saw in the ultrasound, and both of the parents have the ROR2 gene mutation that causes Robinow syndrome. The wife made the decision to end her pregnancy as well. Before her subsequent pregnancy, we advised a data re-analysis.

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