Genetic diagnoses that could have been identified by expanded carrier screening
Stevens BK, Nunley PB, Wagner C, et al. Utility of expanded carrier screening in pregnancies with ultrasound abnormalities. Prenat Diagn. 2022;42:60-78. doi:10.1002/pd.6069.
This series is a thorough retrospective review of patients evaluated in a pediatric genetics clinic from 2014 through 2017. Patients were included if they were evaluated in the first 6 months of life and had a structural abnormality that might be detected on prenatal ultrasonography. The genetic testing results were analyzed and categorized according to types of genetic disorders, with the goal of identifying how many patients might have been identified by expanded carrier screening (ECS) panels.
Study outcomes
A total of 931 charts were reviewed, and 85% (791 of 931) of patients evaluated in the first 6 months of life were determined to have a structural anomaly that might be detected on prenatal ultrasonography. Of those patients, 691 went on to have genetic testing and 32.1% (222 of 691) of them had a diagnostic (pathogenic) genetic testing result related to the phenotype. The types of diagnostic testing results are shown in the FIGURE. Notably, 42 single-gene disorders were detected.
FIGURE Diagnostic test result in pediatric patients evaluated under age 6 months
Of those 222 patients with diagnostic results, there were 8 patients with autosomal recessive and X-linked conditions that could be detected using a 500-gene ECS panel. Five patients could be detected with a 271-gene panel. After nondiagnostic microarray, 11.3% of patients had a condition that could be detected by using a 500-gene ECS panel. The identified conditions included cystic fibrosis, CYP21‐related congenital adrenal hyperplasia, autosomal recessive polycystic kidney disease, Antley‐Bixler syndrome, and Morquio syndrome type A.
Furthermore, the authors conducted a literature review of 271 conditions and found that 32% (88 of 271) of conditions may be associated with ultrasound findings.
Study strengths and limitations
When applying these data to prenatal populations, the authors acknowledge several notable limitations. There is a selection bias toward less-severe phenotypes for many patients choosing to continue rather than to interrupt a pregnancy. Additionally, only 23% of the patients in the study had a microarray and ES, which may lead to an underrepresentation of single-gene disorders and an underestimation of the utility of ECS. Finally, a retrospective classification of structural abnormalities that may be detectable by ultrasonography may not always reflect what is actually reported in prenatal imaging.
However, the work that the authors put forth to evaluate and categorize 931 participants by the results of genetic testing and structural anomalies is appreciated, and the level of detail is impressive for this retrospective chart review. Additionally, the tables itemizing the authors’ review of 271 ECS disorders that may have ultrasonography findings categorized by disorder and system are helpful and quick diagnostic references for clinicians providing prenatal care. ●
This study of potentially detectable prenatal findings from the lens of a pediatric genetics clinic lends an interesting perspective: Exome sequencing is not the primary route to establish a diagnosis; karyotype, microarray, methylation disorders, and triplet repeat disorders all have an established role in the diagnostic toolkit. Keeping in mind the contribution of these modalities to pediatric testing may shorten the diagnostic odyssey to continue pregnancies or help to fully counsel patients on expectations and decision-making after birth.
Carrier screening is not a substitute for diagnostic testing in pregnancy. However, in appropriately selected patients, a broad carrier screening panel may have added utility. ECS can be conducted while awaiting microarray results to help target testing and may be particularly useful for patients who decline diagnostic testing until the postnatal period. It is important to counsel patients that carrier screening is not a diagnostic test, and results will only report likely pathogenic or pathogenic variants, not variants of uncertain significance that may be of clinical relevance. However, our practice has had several insightful diagnoses reached through ECS, in conjunction with microarray testing that allowed for faster and more targeted sequencing and precise fetal diagnosis. This readily available molecular tool (often covered by insurance) deserves a spot in your fetal diagnosis tool belt based on available evidence.