1. Introduction

Congenital anomalies (CAs) occur in about 2–3% of liveborn and 20% of stillborn infants. They are an important cause of neonatal mortality, children morbidity, and long-term disability and

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

so constitute a serious public health and epidemiological problem [1]. A significant proportion of CAs is detected before birth by routine ultrasound examination and other screening techniques [2]. Prenatal identification of CAs can have significant emotional and psychological consequences for parents and affected babies [2]. Therefore, it is imperative to make the right diagnosis as soon and as accurate as possible. Genetic testing in prenatal period is an area with very sensitive and ethically challenging situations [3]. Determining a genetic diagnosis prenatally permits parents to make informative reproductive decisions and to be counseled about possible fetal outcomes [4]. It adds important information for current pregnancy in the terms of full phenotype beyond ultrasonographically detected abnormalities on the one hand and postnatal prognosis on the other [3]. Consequently, it is important to use appropriate genetic testing approach to obtain a specific diagnosis.

epigenetic basis; genes can be silenced or activated by modifications that may depend on the

Genomic Testing for Prenatal Clinical Evaluation of Congenital Anomalies

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With the traditional diagnostic approach using conventional karyotyping and direct molecular genetic testing, the etiology of CAs remains undiagnosed in 65–70%, including cases with multifactorial or polygenic etiology (e.g., isolated neural tube defects or cleft palate), 15–25% is thought to be genetic or genomic—chromosomal in 10–15% and monogenic in 10%—and 10% is thought to be due to environmental factors [4]. Although most CAs are isolated and sporadic; the genetic contribution has long been recognized, and specific genes involved are increasingly being identified. However, the majority of isolated CAs are thought to be caused by a complex interplay of genetic and environmental factors and follow the so-called multifactorial or polygenic inheritance [4, 8, 9]. On the other hand, multiple CAs are often part of a

In the prenatal settings, the frequency of chromosomal abnormalities depends on many factors: the gestational age, type of the anomaly, the number of anomalies, and the combination of anomalies identified [10]. In retrospective series, chromosomal abnormalities were found in 2–18% of cases when isolated and in 18–35% when multiple CAs were prenatally detected on ultrasound [10, 11]. Chromosomal abnormalities are more common in spontaneous abortions

Due to the frequency, morbidity and lethality CAs pose an important public healthcare problem. For the planning of preventive healthcare measures, it is very important to determine the

The following chapters give an overview of the conventional genetic diagnostic approach and

Currently fetal karyotyping and targeted genetic testing are still most commonly used in the genetic diagnostic evaluation of high-risk pregnancies including morphologically abnormal fetus detected by ultrasound examination and positive result of the screening test or due to parental chromosome rearrangement or genetic disorder with a known pathogenic variant. Despite the recent shift of genetic diagnostics toward genomic approach, the conventional diagnostic approach encompassing the karyotyping and targeted molecular genetic testing is

To identify possible genetic causes underlying ultrasonographically detected CAs or positive result of the screening test (nuchal translucency, combined screening test, triple/quadruple hormone test), a full chromosome analysis has been widely used and regarded as the gold

the use of new genomic technologies in the prenatal genetic diagnosis of CAs.

parent of origin or other influences [4].

syndrome, of chromosomal or monogenic etiology.

3. Conventional genetic diagnostic approach

(50%) than in stillbirths (6–13%) [12].

epidemiology and etiology of CAs.

worth noting.

3.1. Karyotyping

In recent years new diagnostic algorithms for prenatal genetic testing are being developed with the advent of new genomic technologies, like molecular karyotyping (comparative genomic hybridization) and next-generation sequencing (NGS). These technologies offer testing options that exceed conventional karyotyping of the fetus and provide better diagnostic yield. Despite the evidence of important additional diagnostic yield of new technologies in the etiology of CAs, they have not been systematically implemented in clinical prenatal diagnostic algorithms in several national healthcare systems.
