Noninvasive prenatal diagnosis of fetal trisomy by allelic ratio analysis using targeted massively parallel sequencing

Abstract

Whether a fetus has an aneuploidy associated with a first chromosome is detected using ratios of alleles detected in a maternal sample having a mixture of maternal and fetal DNA. DNA from the sample is enriched for target regions associated with polymorphic loci and then sequenced. Polymorphic loci (e.g., single nucleotide polymorphisms) in the target regions with fetal-specific alleles are identified on a first chromosome and on one or more reference chromosomes. A first ratio of the fetal-specific alleles and shared alleles is determined for the loci on the first chromosome. A second ratio of the fetal-specific alleles and shared alleles is determined for the loci on the reference chromosome(s). A third ratio of the first and second ratio can be compared to a cutoff to determine whether an aneuploidy is present, and whether the aneuploidy is maternally-derived or paternally-derived.

Description

CROSS-REFERENCES TO RELATED APPLICATION[0001]This application is a non-provisional of and claims the benefit of U.S. Provisional Patent Application No. 61 / 621,454, entitled “NONINVASIVE PRENATAL DIAGNOSIS OF FETAL TRISOMY BY ALLELIC RATIO ANALYSIS USING TARGETED MASSIVELY PARALLEL SEQUENCING,” filed on Apr. 6, 2012, which is herein incorporated by reference in its entirety for all purposes.BACKGROUND[0002]Prenatal screening and diagnosis of fetal aneuploidies, such as trisomy 21 (T21), is an established part of modern obstetrics care. Conventional prenatal screening is built on parameters such as maternal age, sonographic and biochemical markers [1]. Since these parameters are mainly based on phenotypic features, which are essentially epiphenomena associated with the core molecular pathology, their diagnostic performance is usually suboptimal. Pregnancies stratified as high risk by the above screening approaches require further investigation of fetal genetic materials obtained via i...

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Problems solved by technology

These latter procedures carry small, but definite, risk of miscarriage [2].

The large background of maternal DNA represents a challenge for the interrogation of fetal chromosomal status.

However, for the last approach, there are controversies on the effectiveness of formaldehyde treatment because this method could not be replicated consistently by different groups [8-10].

Therefore, the clinical applicability of such a method remains unclear.

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