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. 2023 Nov 23;389(21):2014-2016.
doi: 10.1056/NEJMc2216144.

High-Resolution and Noninvasive Fetal Exome Screening

Harrison Brand  1 , Christopher W Whelan  2 , Michael Duyzend  1 , John Lemanski  1 , Monica Salani  1 , Stephanie P Hao  1 , Isaac Wong  1 , Elise Valkanas  1 , Caroline Cusick  2 , Casie Genetti  3 , Lori Dobson  4 , Courtney Studwell  4 , Kathleen Gianforcaro  4 , Louise Wilkins-Haug  4 , Stephanie Guseh  4 , Benjamin Currall  1 , Kathryn Gray  4 , Michael E Talkowski  5
Affiliations

High-Resolution and Noninvasive Fetal Exome Screening

Harrison Brand et al. N Engl J Med. .
No abstract available

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Figures

Figure 1 (facing page).
Figure 1 (facing page).. Workflow for Noninvasive Fetal Exome Screening with High-Resolution Noninvasive Prenatal Testing.
Panel A shows the process for extracting cell-free DNA (cfDNA) from maternal plasma followed by exome capture (see the Supplementary Appendix). We generated 51 libraries across gestational ages and calculated the fetal fraction (fetal cfDNA ÷ total cfDNA) in each sample. In the box-and-whisker plot on the right, for each trimester, the bold horizontal line indicates the median, the box the interquartile range, and the circles individual data points; whiskers indicate the minimum and maximum values within the range (defined by subtracting 1.5 times the interquartile range from the first quartile and adding the same value to the third quartile). Panel B highlights the methods for detecting novel variants that were developed to account for fetal fraction and shows the corresponding unique allele fractions at each site according to the maternal and fetal genotype combinations present in cfDNA. Each cluster represents a unique maternal–fetal genotype combination. Clusters are colored according to genotypes generated from direct exome sequencing of maternal and fetal DNA. These data highlight the merging of clusters at heterozygous sites in the mother at lower coverage and fetal fraction and the clearly resolved de novo and paternally derived variants (fetal 0/1; maternal 0/0) regardless of fetal fraction. Panel C describes a proof-of-principle application of high-resolution noninvasive fetal screening (NIFS) to 14 pregnancies referred for invasive testing and representative variants of clinical interest, including a likely pathogenic splice variant in COL2A1 (NC_000012.12:g.47982610C→T) in a fetus with micrognathia consistent with autosomal dominant Stickler’s syndrome type 1, a 4-MB pathogenic deletion on chromosome 7 (NC_000007.14:g.155368937-159327017del) in a fetus with multiple congenital anomalies, and a carrier PAH variant (NC_000012.12:g.102866632C→T) that is associated with a risk of phenylketonuria. All the variants were orthogonally validated. WES denotes whole-exome sequencing.
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References

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