Cell-Free DNA Screening for Single-Gene Disorders.

Importance: In pregnancy, cell-free DNA (cfDNA) represents short fragments of placental DNA released into the maternal blood stream through natural cell death. Noninvasive prenatal screening with cfDNA is commonly used in pregnancy to screen for common aneuploidies. This technology continues to evolve, and laboratories now offer cfDNA screening for single-gene disorders. Objective: This article aims to review cfDNA screening for single-gene disorders including the technology, current syndromes for which screening may be offered, limitations, and current recommendations. Evidence Acquisition: Original research articles, review articles, laboratory white papers, and society guidelines were reviewed. Results: Cell-free DNA screening for single-gene disorders is not currently recommended by medical societies. There may be a role in specific circumstances and only after comprehensive pretest counseling. It can be considered in the setting of some fetal ultrasound anomalies, and usually only after diagnostic testing is offered and declined. Conclusions: Given the limitations of using cfDNA screening for single-gene disorders, caution is recommended when considering these tests. It should only be offered with involvement of a reproductive genetic counselor, medical geneticist, or maternal fetal medicine specialist to ensure comprehensive counseling and appropriate utilization.

Novel premature termination codon in the FOXP3 gene as the cause of familial hydrops fetalis in males.

A 19-year-old, G1P0, pregnant person was referred at 20w2d gestation for evaluation due to non-immune hydrops fetalis (NIHF), which was confirmed at the time of evaluation. Amniocentesis was performed at 20 w4d, and FISH, karyotype, chromosomal microarray, and exome sequencing (ES) were ordered. Trio ES identified a novel hemizygous c.142 C > T (p.Arg48*; maternally inherited) variant in the FOXP3 gene, resulting in a premature termination codon and establishing the diagnosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Intrauterine fetal demise (IUFD) was diagnosed at 21w3d. CVS was performed at 12w1d in a subsequent pregnancy (male fetus) and the known familial variant was identified. NIHF was identified at 18w1d. Ultrasound at 19w2d revealed IUFD. This is the first report of this variant in a diagnosis of IPEX syndrome, presenting with NIHF and male fetal demise. Genotype-phenotype correlations are not available in many cases of IPEX syndrome, as the same genotype can be present with variable severity in different individuals. Given the near identical presentations in this family, we anticipate a more severe phenotype with this variant. We propose a novel variant resulting in an early premature termination codon as an explanation for the severe presentation of IPEX syndrome in two successive fetuses in this family.

The COVID-19 pandemic and reproductive genetic counseling: Changes in access and service delivery at an academic medical center in the United States.

The COVID-19 pandemic widely disrupted the delivery of healthcare services, including genetic counseling. To ensure continuity of care, the reproductive genetic counselors at a large academic medical center in the United States rapidly transitioned their practice from 90% in-person patient consultations to a predominantly telehealth model. The present study describes this transition in regard to patient access to genetic counseling and genetic screening. A chart review of patients seen by the reproductive genetic counselors from January 2020 to August 2020 was completed. The time frame included the three months prior to the COVID-19 pandemic and the first five months during COVID-19. Patient demographics and clinical and appointment data were compared between the pre-COVID-19 and during-COVID-19 timeframes. Overall, 88.6% of patients were seen via telehealth during COVID-19 and there was no significant difference based upon patient age (p = .20), indication for appointment (p = .06), or gestational age (p = .06). However, non-English speaking patients were more often seen in-person than by telehealth (p < .001), and more patients residing farther from the clinic were seen via telehealth (p = .004). During-COVID-19 results for prenatal cell-free DNA screening and expanded carrier screening were delayed (p < .001). Additionally, after consenting to screening, patients seen during COVID-19 were more likely to not complete a sample collection for their intended screening when compared to those seen pre-COVID-19 (OR = 6.15, 95% CI = 1.43-26.70, p = .015). Overall, this study supports that access to genetic counseling services and genetic screening can be maintained during a global pandemic like COVID-19. Genetic counselors are well-equipped to pivot swiftly during challenging times; however, they must continue to work to address other barriers to accessing genetic services, especially for non-English speaking populations. Future studies are needed to pose solutions to the obstacles confronted in this service delivery model during a global pandemic.