Prenatal Genetic Diagnosis

Introduction

Chorionic villus sampling

These resources give a general introduction to some of the many new prenatal genetic diagnostic techniques available at different stages of pregnancy. These diagnostic techniques now include Preimplantation Genetic Screening (PGS) in association with the many Assisted Reproductive Technologies, more commonly known as In Vitro Fertilization (IVF).

Diagnosis Links: Prenatal Diagnosis | Pregnancy Test | Amniocentesis | Chorionic villus sampling | Ultrasound | Alpha-Fetoprotein | Pregnancy-associated plasma protein-A | Fetal Blood Sampling | Magnetic Resonance Imaging | Computed Tomography | Preimplantation Genetic Screening | Comparative Genomic Hybridization | Neonatal Diagnosis | Category:Prenatal Diagnosis | Fetal Surgery | Category:Neonatal Diagnosis

Some Recent Findings

European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium set of Guidelines for Best Practice PGD 2010"In 2005, the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium published a set of Guidelines for Best Practice PGD to give information, support and guidance to potential, existing and fledgling PGD programmes. ...Rather than one document that covers all of PGD, the new guidelines are separated into four new documents that apply to different aspects of a PGD programme, i.e. organization of a PGD centre, fluorescence in situ hybridization (FISH)-based testing, amplification-based testing and polar body and embryo biopsy for PGD/preimplantation genetic screening (PGS). " press release Application of a target array comparative genomic hybridization to prenatal diagnosis"In the 132 reference materials, all known genomic alterations were successfully identified. In the 94 clinical samples that were also subjected to conventional karyotyping, three cases of balanced chromosomal aberrations were not detected by aCGH. However, we identified eight cases of microdeletions in the Yq11.23 chromosomal region that were not found by conventional karyotyping. This region harbors the DAZ gene, and deletions may lead to non-obstructive spermatogenesis."

Preimplantation Genetic Screening

A range of techniques including fluorescence in situ hybridization (FISH)-based testing, PCR amplification-based testing and both polar body and embryo biopsy for PGD/preimplantation genetic screening (PGS).

Links: In Vitro Fertilization

Biological Collection Techniques

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  Amniocentesis

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  Chorionic villus sampling

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  Ultrasound

Cordocentesis

Percutaneous umbilical blood sampling (PUBS, fetal blood sampling, umbilical vein sampling) This chromosome analysis test is done at in the 18th week or later of high-risk pregnancies. The technique may be used when either alternative tests (amniocentesis, CVS, ultrasound) are either inconclusive or not achievable (severe oligohydramnios).

The risk of a miscarriage related to the test is about 3 per cent (occurring in 3 in 100 pregnancies).

Coelocentesis

Is a technique of sampling of extracoelomic fluid usually for an early prenatal diagnostic technique.

Fetal Fibronectin

As a prenatal diagnostic test, a positive fetal fibronectin test result can indicate a higher risk of preterm delivery, but may also has false positive results. The negative result is more reliable as an indicator of reduced risk of preterm birth.

(fFN) is an extracellular matrix glycoprotein produced by fetal cells. Fetal fibronectin appears to act as an adhesive between the interface of the chorion and the decidua (fetal membrane and uterine lining).

Fluorescence In Situ Hybridization (FISH)

This technique has several diagnostic and screening applications including:

• embryo sexing for X-linked diseases
• embryo sexing for social reasons (gender selection/family balancing)
• inherited chromosome rearrangements
• aneuploidy screening (PGS)

The following information for probe selection is based upon the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium set of Guidelines for Best Practice PGD. The guidelines were first published in 2005 and recently updated in 2010.

Links: ESHRE publishes new PGD guidelines

Embryo Sexing

A probe set containing at least probes specific for the centromere regions of the X and Y chromosomes, and one autosome.

Chromosome Rearrangements

A probe set should at least contain sufficient probes to detect all expected unbalanced forms of the chromosomal rearrangement.

Comparative Genomic Hybridization

This new test under development is based upon microarray-based comparative genomic hybridization (array CGH).

All fetal cells should have complete copies of maternal and paternal genomes. The test compares regions of fetal DNA that deviate from this "pattern" due to either too much or too little DNA, alterations reflect regions of the genome that are either copied or deleted. These genetic changes may therefore cause disease. (More? Prenatal Diagnosis - Comparative Genomic Hybridization)

Gene Tests

A new site developed by NIH "GeneTests" provides medical genetics information resources available at no cost to all interested persons. It contains educational information, a directory of genetic testing laboratories and links to other databases such as OMIM.

Links: GeneTests

Ethics of Testing

Major developmental abnormalities detected early enough can be resolved far more easily than those discovered late in a pregnancy.

What are the ethical questions that are raised by prenatal testing? Future individual rights or parents rights? But what about diseases, like Huntington's, where a diagnostic test can be made but there are no current treatments for the postnatal (95% of cases adult onset) disease?

Huntington's disease

Guidelines for the molecular genetics predictive test

Recommendation 2.1 "the test is available only to individuals who have reached the age of majority."

Recommendation 7.2 "the couple requesting antenatal testing must be clearly informed that if they intend to complete the pregnancy if the fetus is a carrier of the gene defect, there is no valid reason for performing the test."

(excerpt from: IHA and the World Federation of Neurology Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease.)

Prenatal Diagnosis Terms

• false negative rate - The proportion of pregnancies that will test negative given that the congenital anomaly is present.
• false positive rate - The proportion of pregnancies that will test positive given that the congenital anomaly is absent.
• negative predictive value - The probability that a congenital anomaly is absent given that the prenatal screening test is negative.
• positive predictive value - The probability that a congenital anomaly is present given that the prenatal screening test is positive.
• pre-implantation genetic diagnosis - (PGD) a screening procedure for embryos produced through in vitro fertilisation (IVF) for genetic diseases that would generate developmental abnormalities or serious postnatal diseases.
• prenatal screening sensitivity - (detection rate) The probability of testing positive on a prenatal screening test if the congenital anomaly is present.
• prenatal screening specificity - The probability of testing negative on a prenatal screening test if the congenital anomaly is absent.

References

Journals

• Journal - Prenatal diagnosis

Reviews

Gary Fruhman, Ignatia B Van den Veyver Applications of array comparative genomic hybridization in obstetrics. Obstet. Gynecol. Clin. North Am.: 2010, 37(1);71-85, Table of Contents PMID:20494259

Articles

Justine Coppinger, Sarah Alliman, Allen N Lamb, Beth S Torchia, Bassem A Bejjani, Lisa G Shaffer Whole-genome microarray analysis in prenatal specimens identifies clinically significant chromosome alterations without increase in results of unclear significance compared to targeted microarray. Prenat. Diagn.: 2009, 29(12);1156-66 PMID:19795450

Anthony J Schaeffer, June Chung, Konstantina Heretis, Andrew Wong, David H Ledbetter, Christa Lese Martin Comparative genomic hybridization-array analysis enhances the detection of aneuploidies and submicroscopic imbalances in spontaneous miscarriages. Am. J. Hum. Genet.: 2004, 74(6);1168-74 PMID:15127362

Search PubMed

Search PubMed: Prenatal Genetic Diagnosis | Prenatal Genetic Screening

Glossary Links

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Dr Mark Hill 2013, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G