Louise Wilkins-Haug1, Chengsheng Zhang2, Eliza Cerveira2, Mallory Ryan2, Adam Mil-Homens2, Qihui Zhu2, Honey Reddi2, Charles Lee2, Diana W Bianchi3,4. 1. Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, USA. 2. Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. 3. Mother Infant Research Institute, Tufts Medical Center, Boston, MA, USA. 4. Prenatal Genomics and Therapy Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Abstract
OBJECTIVE: Maternal plasma cell-free DNA (cfDNA) analysis is a powerful screening tool for Down syndrome. In a pilot series, we examined biologic causes of discordance between the cfDNA test results and the fetal karyotype. We also explored the feasibility of obtaining trio biospecimens by using parental engagement. METHODS: A convenience sample of women with discordant cfDNA results were recruited by their care providers. We provided shipping materials and instructions for biospecimen collection. Maternal, newborn, and placental samples were examined with droplet digital PCR. RESULTS: Thirteen of 15 women successfully had biospecimens obtained remotely. High-quality DNA was extracted in 12 of 13 women. Presumed biologic etiologies for discordance were identified in 7 of 12 women: 3 cases from additional clinical review (male renal transplant, vanishing twin, and colon cancer) and 4 cases from additional laboratory investigation using droplet digital PCR (3 with confined placental mosaicism and 1 with true fetal mosaicism). CONCLUSIONS: Understanding the biology behind cfDNA-fetal karyotype discordancy is useful for follow-up clinical care. Our study suggests that most cases could be resolved by using a trio biospecimen protocol and parental involvement. To improve accuracy, additional sequencing of biospecimens will be required.
OBJECTIVE: Maternal plasma cell-free DNA (cfDNA) analysis is a powerful screening tool for Down syndrome. In a pilot series, we examined biologic causes of discordance between the cfDNA test results and the fetal karyotype. We also explored the feasibility of obtaining trio biospecimens by using parental engagement. METHODS: A convenience sample of women with discordant cfDNA results were recruited by their care providers. We provided shipping materials and instructions for biospecimen collection. Maternal, newborn, and placental samples were examined with droplet digital PCR. RESULTS: Thirteen of 15 women successfully had biospecimens obtained remotely. High-quality DNA was extracted in 12 of 13 women. Presumed biologic etiologies for discordance were identified in 7 of 12 women: 3 cases from additional clinical review (male renal transplant, vanishing twin, and colon cancer) and 4 cases from additional laboratory investigation using droplet digital PCR (3 with confined placental mosaicism and 1 with true fetal mosaicism). CONCLUSIONS: Understanding the biology behind cfDNA-fetal karyotype discordancy is useful for follow-up clinical care. Our study suggests that most cases could be resolved by using a trio biospecimen protocol and parental involvement. To improve accuracy, additional sequencing of biospecimens will be required.
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