Probabilistic method for detecting copy number variation in a fetal genome using maternal plasma sequencing.

Ladislav Rampášek,Michael Brudno,Aryan Arbabi

doi:10.1093/bioinformatics/btu292

Ladislav Rampášek, Michael Brudno + Show 1 more

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https://doi.org/10.1093/bioinformatics/btu292

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Abstract

Motivation: The past several years have seen the development of methodologies to identify genomic variation within a fetus through the non-invasive sequencing of maternal blood plasma. These methods are based on the observation that maternal plasma contains a fraction of DNA (typically 5–15%) originating from the fetus, and such methodologies have already been used for the detection of whole-chromosome events (aneuploidies), and to a more limited extent for smaller (typically several megabases long) copy number variants (CNVs).Results: Here we present a probabilistic method for non-invasive analysis of de novo CNVs in fetal genome based on maternal plasma sequencing. Our novel method combines three types of information within a unified Hidden Markov Model: the imbalance of allelic ratios at SNP positions, the use of parental genotypes to phase nearby SNPs and depth of coverage to better differentiate between various types of CNVs and improve precision. Our simulation results, based on in silico introduction of novel CNVs into plasma samples with 13% fetal DNA concentration, demonstrate a sensitivity of 90% for CNVs >400 kb (with 13 calls in an unaffected genome), and 40% for 50–400 kb CNVs (with 108 calls in an unaffected genome).Availability and implementation: Implementation of our model and data simulation method is available at http://github.com/compbio-UofT/fCNV.Contact: brudno@cs.toronto.edu

Highlights

Until recently, the prenatal analysis of a fetal genome required samples directly obtained from the fetus by invasive procedures like chorionic villus sampling or amniocentesis, where amniotic fluid is sampled from around the developing fetus
We introduce a novel model for noninvasive prenatal identification of de novo copy number variants (CNVs) with increased sensitivity compared with methods published so far
We introduce a novel probabilistic method for the identification of de novo CNVs from maternal blood plasma sequencing with largely increased sensitivity compared with methods published so far

Summary

Introduction

The prenatal analysis of a fetal genome required samples directly obtained from the fetus by invasive procedures like chorionic villus sampling or amniocentesis, where amniotic fluid is sampled from around the developing fetus. Foremost, it carries a non-trivial risk of miscarriage [estimated procedure-related fetal loss rate is 0.6–1% (Douglas et al, 2007)], and is refused by a fraction of patients. Amniocentesis cannot be performed too early, as the risk of miscarriage rises significantly, and is typically indicated for the 15th week of pregnancy, outside of the time-frame for the safest abortion options (512 weeks) and leaving only limited time for follow-up analysis. Amniocentesis is typically performed only to confirm or reject a diagnosis if a genetic disease is suspected, e.g. high likelihood of Down syndrome based on prenatal ultrasound

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