In Principle Method for Noninvasive Determination of the Fetal Genome

Christina Fan,Stephen Quake

doi:10.1038/npre.2010.5373.1

Christina Fan, Stephen Quake

Open Access

https://doi.org/10.1038/npre.2010.5373.1

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Abstract

AbstractWe illustrate the concept of noninvasive determination of the fetal genome by shotgun sequencing maternal plasma. The approach is based on molecular counting of alleles in maternal cell-free DNA: the inheritance of paternal haplotypes can be determined by counting paternal specific alleles present on each of the paternal haplotypes; the inheritance of maternal haplotypes can be revealed by counting the alleles on each maternal haplotype and determining the relative representation of the two maternal haplotypes. The concept was experimentally proven by sequencing a synthetic mixture of genomic DNA samples from a child and her mother, whose whole-genome haplotypes (defined by ~800,000 SNPs), together with those of the father, were previously determined. Light sequencing (0.25x) of such sample containing ~16% child’s DNA enabled the inheritance of parental haplotypes to be correctly resolved over most part of the genome, and partially resolved when prior knowledge of paternal whole-genome haplotypes is absent. Translating this approach to maternal plasma DNA samples, together with increased sequencing depth and phase knowledge of additional numbers of parental SNPs, should enable clinically practical sequencing of the fetal genome.

Highlights

Prenatal diagnosis of many genetic diseases requires measurement of fetal genotypes
Noninvasive measurement of fetal genotypes that are heterozygous in the fetus and homozygous in the mother is relatively trivial, since one only needs to detect the presence of an allele that is not present in the mother
Noninvasive measurement of fetal genotypes that are heterozygous in the mother is much more challenging but has important applications, especially for the diagnosis of autosomal recessive diseases

Summary

Introduction

Prenatal diagnosis of many genetic diseases requires measurement of fetal genotypes. Noninvasive measurement of fetal genotypes that are heterozygous in the fetus and homozygous in the mother is relatively trivial, since one only needs to detect the presence of an allele that is not present in the mother. Noninvasive measurement of fetal genotypes that are heterozygous in the mother is much more challenging but has important applications, especially for the diagnosis of autosomal recessive diseases. In situations where both the mother and father are carriers of a disease associated locus, it would be of interest to determine if the fetus has inherited both copies of the recessive allele. Determining fetal genotypes in such a situation is difficult because only a small portion (

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