Opening Pandora's box: abnormal genetic carrier screening and need for lifetime follow-up

Expanded carrier screening (ECS) is rising in popularity because of its application in a diverse population, its decreasing cost, and efficiency.¹ However, it has traditionally been used to assess fetal risk. The next generation sequencing ECS panel offered at our academic medical center consists of 283 genes associated with hereditary disorders. Of those, 20 (7.1%) are autosomal recessive conditions, notable for variable expression of the clinical phenotype in heterozygous carriers, which may increase maternal risk for malignancy, bleeding, cardiovascular, or rheumatologic disease. Another 21 (7.4%) are X-linked conditions. We aimed to evaluate the prevalence of variants that have a potential for maternal phenotypic expression and whether identification of specific variants prompted patients to pursue further care in our health system, namely comprehensive genetic counseling and further healthcare consults when recommended.

An institutional review board-approved descriptive retrospective cohort study was performed in a New York City academic medical center at which reproductive aged women were offered universal ECS from 2018 to 2021 by their provider, inclusive of obstetrician-gynecologists, maternal-fetal medicine physicians, and genetic counselors. Pretest counseling was performed by the ordering provider. Patients found to carry mutations with the potential for maternal phenotypic expression were contacted by genetic counselors regarding their clinical risks. In addition, patients who were carriers for factor XI deficiency, Bernard Soulier syndrome, ataxia telangectesia, fumarase deficiency, Nijmegen breakage syndrome, Duchenne muscular dystrophy, and familial hypercholesterolemia were advised to seek specialized healthcare pertaining to their clinical risk. The genetic counseling summary was placed in the electronic medical records (EMRs) so that the primary provider could view the findings. Through our EMRs, we evaluated the rates of healthcare uptake among these patients for at least 1 year after delivery.

In total, 168 of 1184 (14.2%) patients were identified as carriers of mutations with a potential for maternal phenotypic expression. Of these, 156 (93%) were pregnant and 12 (7%) were preconception. Of those patients, 143 (85%) were carriers of autosomal recessive traits (Figure 1), whereas 22 of 168 (13%) patients were carriers of X-linked conditions (Figure 2) and 3 of 168 (2%) patients carried both autosomal recessive traits and X-linked conditions. Of these carriers, 132 of 168 (78.6%) patients underwent genetic counseling. The most common heterozygous mutations were sickle cell trait (25.6%), thalassemia (alpha and/or beta) trait (14.2%), factor XI deficiency (4.7%), dystrophic epidermolysis bullosa (4.2%), and Alport syndrome (4.1%). Two patients were diagnosed as homozygous carriers of nonclassical congenital adrenal hyperplasia. During the study period, 23 of 168 (13.6%) patients were heterozygous for specific pathogenic variants (inclusive of factor XI, Bernard Soulier syndrome, ataxia telangectesia, fumarase deficiency, Nijmegen breakage syndrome, Duchenne muscular dystrophy, and familial hypercholesterolemia) and were advised to seek specialized healthcare pertaining to these findings. Of these, 20 (87.0%) received genetic counseling with standardized recommendations, however, only 4 of 23 (17%) patients pursued the recommended referrals during our study period.

This study described the follow-up rates among patients identified as carriers of conditions with the potential for maternal phenotypic expression using ECS. We observed that 14.2% of patients who underwent ECS were identified as carriers of genetic mutations with the potential for maternal phenotypic expression, and of the 23 who were recommended specific care because a pathogenic variant was identified, only 17.4% of patients followed the recommendations. We believe that as ECS implementation becomes widespread, more maternal carriers with clinical risk to themselves will be identified. Therefore, as we open this Pandora's box, the burden of counseling and follow-up must be addressed.