Noninvasive Whole-Genome Sequencing of a Human Fetus

Sci Transl Med 6 June 2012:
Vol. 4, Issue 137, p. 137ra76
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3004323

• Research Article

Genomics

Noninvasive Whole-Genome Sequencing of a Human Fetus

1. Jacob O. Kitzman¹,*,
2. Matthew W. Snyder¹,
3. Mario Ventura¹,²,
4. Alexandra P. Lewis¹,
5. Ruolan Qiu¹,
6. LaVone E. Simmons³,
7. Hilary S. Gammill³,⁴,
8. Craig E. Rubens⁵,⁶,
9. Donna A. Santillan⁷,
10. Jeffrey C. Murray⁸,
11. Holly K. Tabor⁵,⁹,
12. Michael J. Bamshad¹,⁵,
13. Evan E. Eichler¹,¹⁰ and
14. Jay Shendure¹,*

+ Author Affiliations

1. ¹Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
2. ²Department of Biology, University of Bari, Bari 70126, Italy.
3. ³Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, USA.
4. ⁴Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
5. ⁵Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA.
6. ⁶Global Alliance to Prevent Prematurity and Stillbirth, an initiative of Seattle Children’s, Seattle, WA 98101, USA.
7. ⁷Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.
8. ⁸Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
9. ⁹Treuman Katz Center for Pediatric Bioethics, Seattle Children’s Research Institute, Seattle, WA 98101, USA.
10. ¹⁰Howard Hughes Medical Institute, Seattle, WA 98195, USA.

1. ↵*To whom correspondence should be addressed. E-mail: shendure@uw.edu (J.S.); kitz@uw.edu (J.O.K.)

Abstract

Analysis of cell-free fetal DNA in maternal plasma holds promise for the development of noninvasive prenatal genetic diagnostics. Previous studies have been restricted to detection of fetal trisomies, to specific paternally inherited mutations, or to genotyping common polymorphisms using material obtained invasively, for example, through chorionic villus sampling. Here, we combine genome sequencing of two parents, genome-wide maternal haplotyping, and deep sequencing of maternal plasma DNA to noninvasively determine the genome sequence of a human fetus at 18.5 weeks of gestation. Inheritance was predicted at 2.8 × 10⁶ parental heterozygous sites with 98.1% accuracy. Furthermore, 39 of 44 de novo point mutations in the fetal genome were detected, albeit with limited specificity. Subsampling these data and analyzing a second family trio by the same approach indicate that parental haplotype blocks of ~300 kilo–base pairs combined with shallow sequencing of maternal plasma DNA is sufficient to substantially determine the inherited complement of a fetal genome. However, ultradeep sequencing of maternal plasma DNA is necessary for the practical detection of fetal de novo mutations genome-wide. Although technical and analytical challenges remain, we anticipate that noninvasive analysis of inherited variation and de novo mutations in fetal genomes will facilitate prenatal diagnosis of both recessive and dominant Mendelian disorders.

• Copyright © 2012, American Association for the Advancement of Science

Citation: J. O. Kitzman, M. W. Snyder, M. Ventura, A. P. Lewis, R. Qiu, L. E. Simmons, H. S. Gammill, C. E. Rubens, D. A. Santillan, J. C. Murray, H. K. Tabor, M. J. Bamshad, E. E. Eichler, J. Shendure, Noninvasive Whole-Genome Sequencing of a Human Fetus. Sci. Transl. Med. 4, 137ra76 (2012).

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