Single gene disorders remain a leading cause of morbidity and mortality in newborns and children, but carrier screening for such disorders was limited until recent advances in DNA sequencing, wrote Vivienne Souter, MD, of Natera in Austin, Tex., and colleagues.
Identifying single gene disorders in carrier screening also includes the discovery of genetic variants that could affect the carrier parent during pregnancy, they said.
In a study published in Obstetrics and Gynecology, the researchers reviewed data from 91,637 female patients who underwent testing via a 274-gene carrier screening panel. The median age of the participants was 32.8 years, and approximately half were pregnant at the time of the testing.
Based on previously published reports, the researchers identified 12 genes with potential for carrier manifestations during pregnancy; of these, 9 had manifestations whether or not the fetus was affected by the genetic condition (ABCB11, COL4A3, COL4A4, COL4A5, DMD, F9, F11, GLA, and OTC) and 3 had manifestations only if the fetus was affected by the condition (CPT1A, CYP19A1, and HADHA).
Overall, 66% of the tests were positive for at least one of the 274 genes; the frequency of potentially pathogenic variants for the 12 genes that could manifest as complications during pregnancy ranged from 1 in 117 individuals for the F11 gene to 1 in 8,331 for the OTC gene.
A total of 2.3% of the participant tests were associated a pathogenic or likely pathogenic variant in at least 1 of the 12 genes, which accounted for 3.5% of all positive samples, and 2.0% were identified as carriers for 1 of the 9 genes that could affect women during pregnancy regardless of fetal genetic status.
“People of Ashkenazi Jewish heritage were over-represented in the carrier group, representing 6.0% of carriers but only 1.9% of the entire study cohort,” the researchers noted.
Manifestations related to the 12 genes included cardiomyopathy, hemorrhage, gestational hypertensive disorders, cholestasis of pregnancy, acute fatty liver, hyperammonemic crisis, and maternal virilization.
“The reported incidence of pregnancy complications in carriers ranged from 10% to 62% depending on the gene involved, but information was limited for most of the conditions,” and published literature identified management recommendations for 11 of the 12 genes, the researchers wrote.
The findings were limited by several factors including the use of cases received by the laboratory, which might have yielded more women with above-average risk because of family history, the researchers noted. Other limitations included a lack of data on further evaluation or counseling after the screening, and the lack of separation of the results according to the specific variant, they said. Also, the study population was limited to those who had access to carrier screening, and may not be generalizable to the population at large.
However, the results support the value of carrier screening, and pretest counseling should inform individuals of the potential identification of genes that might increase their risk of complications during pregnancy, the researchers said.
“Obstetric care professionals should also be aware that carrier status for certain conditions can be important for risk assessment and management in pregnancy,” and post-test genetic counseling, follow-up testing, and clinical management can help reduce risks, which could potentially be identified prior to pregnancy, they concluded.
The study was funded by Natera. Dr. Souter is an employee of Natera.