A recent study examined how atypical findings of a cell-free DNA (cfDNA) test can prompt additional testing and lead to a deeper understanding of medical conditions that may be affecting a fetus, placenta or pregnant patient.
For families affected by fetal and neonatal alloimmune thrombocytopenia (FNAIT), cell-free DNA (cfDNA) testing is increasingly relevant because fetal DNA circulating in maternal blood can be analyzed to determine whether a fetus carries a human platelet antigenHuman platelet antigen Proteins found on the surface of platelets. Incompatibility between maternal and fetal human platelet antigens can trigger FNAIT. (HPAHuman platelet antigen Proteins found on the surface of platelets. Incompatibility between maternal and fetal human platelet antigens can trigger FNAIT.) that the mother’s immune system may recognize as foreign. Previous research has established noninvasive fetal HPA genotypingGenotyping A laboratory test that identifies which platelet antigens a person carries. Often used to confirm HPA incompatibility and assess recurrence risk. as a way to assess FNAITFetal and neonatal alloimmune thrombocytopenia A rare condition in which a mother’s immune system attacks fetal platelets, leading to dangerously low platelet levels before and/or after birth. risk without obtaining fetal DNA through procedures such as amniocentesis or chorionic villus sampling.
The recent study, published in Genetics in Medicine, analyzed 204 cases in which prenatal cfDNA screening produced an atypical result and follow-up testing was performed. Half of the cases, 102 of 204 (50%), had at least one abnormal finding. Among those 102 cases, 55 findings were pathogenic, 18 were variants of uncertain significance and eight were likely benign. Most abnormal results, 87 of 102, were related to the atypical cfDNA finding.
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The investigators reviewed more than 10 years of prenatal, newborn and maternal testing. Copy number variations, which involve missing or extra sections of DNA, were the most common finding, occurring in 38 of 102 abnormal cases (37.3%). Aneuploidy, involving an extra or missing chromosome, occurred in 37 cases (36.3%), while chromosome rearrangements were identified in 20 (19.6%). Other findings included uniparental disomy and regions of homozygosity associated with consanguinity.
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The location of the abnormality was not always the same as the suspected source of the cfDNA result. Prenatal testing was performed in 147 of 204 cases (72.1%), maternal testing in 63 (30.9%) and newborn testing in 44 (21.6%). When cfDNA suggested a maternal origin and maternal testing was performed, 12 of 14 cases (85.7%) were abnormal. Results suggesting a fetal or placental origin were confirmed as related findings in 11 of 38 cases (25.6%).
“Overall, this large-scale analysis showed the efficacy of follow-up testing after atypical cfDNA results,” explained the authors of the research. They continued, “However, our study is limited by its retrospective nature and non-standard ordering practices.”
For families dealing with FNAIT, the study does not provide information about HPA testing or FNAIT diagnosis specifically. Its relevance is in demonstrating the complexity of cfDNA results: DNA detected in maternal blood can provide information about the fetus or placenta but can also point to a genetic finding in the pregnant person. Similar principles are important when interpreting noninvasive fetal HPA testing for FNAIT, where accurately determining the fetal genotype can help establish whether a fetus is at risk.
The researchers found that atypical results represented 5.7% of cfDNA follow-up testing during the first five years studied and 20.1% during the following five years. They said these findings support investigating atypical results rather than dismissing them and emphasized that more information about the suspected origin and type of finding could help clinicians select appropriate follow-up testing. For patients and families, that can mean clearer answers about whether an unexpected cfDNA result reflects the fetus, placenta or pregnant person and what additional testing may be appropriate.
