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Clin Chem. 2017 Feb;63(2):513-524. doi: 10.1373/clinchem.2016.268375. Epub 2016 Dec 8.

Universal Haplotype-Based Noninvasive Prenatal Testing for Single Gene Diseases.

Author information

  • 1Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 2Centre for Research into Circulating Fetal Nucleic Acids, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
  • 3Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 4Department of Pediatrics, Icahn School of Medicine at Mount Sinai, NY.
  • 5Department of Obstetrics and Gynaecology, Royal Free London NHS Foundation Trust, London, UK.
  • 6Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, UK.
  • 7Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China; rossachiu@cuhk.edu.hk.

Abstract

BACKGROUND:

Researchers have developed approaches for the noninvasive prenatal testing of single gene diseases. One approach that allows for the noninvasive assessment of both maternally and paternally inherited mutations involves the analysis of single nucleotide polymorphisms (SNPs) in maternal plasma DNA with reference to parental haplotype information. In the past, parental haplotypes were resolved by complex experimental methods or inferential approaches, such as through the analysis of DNA from other affected family members. Recently, microfluidics-based linked-read sequencing technology has become available and allows the direct haplotype phasing of the whole genome rapidly. We explored the feasibility of applying this direct haplotyping technology in noninvasive prenatal testing.

METHODS:

We first resolved the haplotypes of parental genomes with the use of linked-read sequencing technology. Then, we identified SNPs within and flanking the genes of interest in maternal plasma DNA by targeted sequencing. Finally, we applied relative haplotype dosage analysis to deduce the mutation inheritance status of the fetus.

RESULTS:

Haplotype phasing and relative haplotype dosage analysis of 12 out of 13 families were successfully achieved. The mutational status of these 12 fetuses was correctly classified.

CONCLUSIONS:

High-throughput linked-read sequencing followed by maternal plasma-based relative haplotype dosage analysis represents a streamlined approach for noninvasive prenatal testing of inherited single gene diseases. The approach bypasses the need for mutation-specific assays and is not dependent on the availability of DNA from other affected family members. Thus, the approach is universally applicable to pregnancies at risk for the inheritance of a single gene disease.

PMID:
27932412
DOI:
10.1373/clinchem.2016.268375
[PubMed - in process]
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