Skip to main content

Conference Program

Subpage Hero

Loading

Use of cell-free DNA for prenatal diagnosis of single gene disorders: experience of a single tertiary care center  

Prenatal Genetics
  • Primary Categories:
    • Prenatal Genetics
  • Secondary Categories:
    • Prenatal Genetics
Introduction:
Cell free DNA (cfDNA) offers opportunity for prenatal genetic screening and diagnosis of single gene disorders, particularly when invasive testing options are not pursued. Despite its growing use, there is little guidance for how this technology should be utilized to screen or diagnose single gene disorders (SGD) in the fetus. As adoption of this technology increases, questions regarding indications, best practices, and diagnostic yield emerge. The purpose of this study is to describe indications for and diagnostic yield of cfDNA for the detection of SGD.

Methods:
Retrospective chart review of patients who elected to have cfDNA for SGD following ultrasound and comprehensive genetic counseling. For those with fetal abnormalities as the presenting indication, patients at our center received counseling immediately after ultrasound by a maternal fetal medicine specialist (MFM) and genetic counselor (GC) with option of same-day chorionic villus sampling or amniocentesis.  We began offering cfDNA for SGD in 06/2018 through the Vistara™ platform at Natera. Charts were reviewed between 06/2018 to 09/2023 for indications for testing, test results, and diagnostic yield. Data were analyzed using descriptive statistics. This study was approved by our Institutional Review Board, IRB #23-2543.  

Results:
Vistara™ was ordered for 57 cases in which ultrasound-detected fetal abnormalities were present or the family history indicated screening. Of the total cohort, 6 (11%) resulted in miscarriage or fetal demise, 1 (2%) had a termination of pregnancy, 2 (4%) had a neonatal demise, and 18 (32%) were lost to care. Six tests identified a pathogenic variant (6/57, 11%); 47 (82%) were negative and 4 (7%) provided ‘no result.’ Among the positive cases, 2/6 (33%) identified pathogenic variants consistent with tuberous sclerosis complex (TSC), 2/6 (33%) identified pathogenic variants consistent with RASopathies, and 2/6 (33%) identified pathogenic variants associated with osteogenesis imperfecta (OI). Vistara™ was sent most frequently for the following indications (percent frequency in parentheses, not exclusive): multiple anomaly phenotypes (21%), cystic hygroma (18%), congenital heart disease (11%), increased nuchal translucency (9%), family history of SGD (confirmed molecular etiology) (9%), short long bones <5%ile (5%), advanced paternal age (4%), cardiac rhabdomyoma (4%), family history of SGD without a known molecular etiology (CHARGE and Ehlers-Danlos syndrome, type unknown; 4%). Less frequent indications (2% and less) included: ventriculomegaly, bowed long bones, limb anomalies, increased nuchal fold, pleural effusion, renal anomalies.



Diagnostic yield by indication was highest for the following indications: cardiac rhabdomyoma (2/2, 100%), family history of genetic condition with confirmed molecular etiology (which included RASopathy, thanatophoric dysplasia, and OI) (2/5, 40%), cystic hygroma (1/10, 10%), multiple fetal anomalies (1/12, 8%). Of those patients that had a positive Vistara™, only 1/6 (16%) had confirmatory diagnostic testing during pregnancy; remaining patients had confirmatory genetic testing on cord blood after birth. This indicates a positive predictive value of 100% in this cohort. Seven (7/57, 12%) received alternative diagnoses through other cell-free DNA based testing, direct DNA testing after invasive procedure, or postnatal genetic testing via cord blood.

Conclusion:
Diagnostic yield of cfDNA for SGD using the Vistara™ platform by Natera resulted in an 11% diagnostic yield when fetal ultrasound abnormalities, family history of SGD with or without a known molecular etiology, and/or advanced paternal age are present. A significant proportion of the cohort (12%) had other genetic diagnoses that required alternative testing.  Our overall diagnostic yield (11%) is substantially higher than when Vistara™ is used in an unselected cohort (PMID 34358384). Future studies are required to determine best practices for use of cfDNA for SGD including use in unselected versus selected populations, impact on pregnancy outcomes, and patient perspectives on this technology.

Agenda

Sponsors