Grand Rounds

Can we Sequence an Entire Fetal Genome from an Amniocentesis Sample?

BACKGROUND AND PURPOSE:

There are potentially thousands of genes where loss of function could impact health
There have been limited studies using high coverage whole genome sequencing (WGS) on fetal cells and cell free DNA obtained through amniocentesis
Mao et al. (Clinical Chemistry, 2018) aimed to acquire whole-genome sequence of a fetus from either cellular or cell-free DNA (cfDNA) of an amniotic sample

There were 31 amniocentesis samples
DNA was obtained from two sources
- cfDNA (DNA freely circulating in the amniotic fluid) outside of cells
- Whole cells in the amniotic fluid
DNA was sequenced to approximately 50x genome coverage

Up to 97% of the fetal genome could be confidently called from freely circulating DNA in the amniotic fluid or the cell pellet after spinning down the amniotic fluid
- WGS could be added to leftover amniotic fluid specimens without disturbing current standard of care
Two fetal genomes were found to harbor potentially detrimental variants in two genes
- Chromodomain helicase DNA binding protein 8 (CHD8)
- LDL receptor-related protein 1 (LRP1)
CHD8 and LRP1 are associated with higher risk for autism spectrum disorder and keratosis pilaris atrophicans, respectively
Drug sensitivities and carrier information of fetuses was also collected

Whole genome sequences of 31 fetuses demonstrated that the cfDNA or DNA from the cell pellet can be analyzed with little difference in quality
This authors suggest that accurate and complex fetal analyses could soon become available

Note: ACOG and other professional associations consider WGS appropriate in research settings only (see ‘Related ObG Topics’ below)

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