Clinical chemistry · 2026
Simultaneous Prenatal cfDNA Screening of Aneuploidy, Recessive Single-Gene Conditions, and Fetomaternal Blood Compatibility.
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Wang Juexiao Sherry, Battey C J, Trettin Kyle, Patel Ravi, Srinivasan Anu, Saikumar Janani, Kushnoor Divya, Habermeyer Ben F, Ganesh Sangita, Xu Nafei, Friedrich Nathaniel, Pierson Summer, Wan Helen, LaBreche Heather, Gould Genevieve M, Muzzey Dale
Аннотация
BACKGROUND: The provision of prenatal genetic screening in 3 core clinical contexts-recessive conditions, aneuploidy, and serological incompatibility-involves multiple tests across reproductive partners. This complexity limits utilization and impairs adherence to guideline-recommended care, particularly in carrier screening, where male partners are frequently not tested when a female carrier is identified. Here, we describe the analytical validation of a fetomaternal integrated recessive, serological, and trisomy genetic screen (FIRSTGENE), a single assay that harnesses in silico fragment-length trajectory analysis to evaluate all 3 contexts simultaneously, identifying clinically relevant variants in both the mother and the fetus without requiring a paternal sample.
METHODS: FIRSTGENE screens singleton pregnancies for mutations in 20 recessive genes; RhD compatibility; aneuploidies in chromosomes 13, 18, 21, X, and Y; and 22q11.2 microdeletion. Each part of the test was individually validated using a relevant subset of plasma samples from a curated collection (478 total samples from 456 patients) and 93 cell-line mixtures digested to resemble maternal and fetal cell-free DNA.
RESULTS: FIRSTGENE demonstrated ≥98.2% sensitivity and ≥99.0% specificity for fetal alleles in recessive-disease genes in plasma and cell lines; 100% sensitivity and specificity for RhD compatibility in plasma; 100% sensitivity and ≥99.8% specificity for fetal chromosomal abnormalities in plasma; and ≥99.9% sensitivity and specificity for maternal alleles in recessive-disease genes in plasma.
CONCLUSIONS: FIRSTGENE demonstrated high analytical sensitivity and analytical specificity for each component of the assay. Its capability to generate multiple prenatal screening results from a single blood draw may improve the efficiency and accessibility of prenatal genetic screening.
METHODS: FIRSTGENE screens singleton pregnancies for mutations in 20 recessive genes; RhD compatibility; aneuploidies in chromosomes 13, 18, 21, X, and Y; and 22q11.2 microdeletion. Each part of the test was individually validated using a relevant subset of plasma samples from a curated collection (478 total samples from 456 patients) and 93 cell-line mixtures digested to resemble maternal and fetal cell-free DNA.
RESULTS: FIRSTGENE demonstrated ≥98.2% sensitivity and ≥99.0% specificity for fetal alleles in recessive-disease genes in plasma and cell lines; 100% sensitivity and specificity for RhD compatibility in plasma; 100% sensitivity and ≥99.8% specificity for fetal chromosomal abnormalities in plasma; and ≥99.9% sensitivity and specificity for maternal alleles in recessive-disease genes in plasma.
CONCLUSIONS: FIRSTGENE demonstrated high analytical sensitivity and analytical specificity for each component of the assay. Its capability to generate multiple prenatal screening results from a single blood draw may improve the efficiency and accessibility of prenatal genetic screening.