2. The epidemiology and etiology of CA

A CA is defined as any structural anomaly present at birth. Major CAs are anomalies that have medical, surgical, or cosmetic significance and occur in about 2–3% of liveborn and 20% of stillborn infants [1]. Thus, CAs are more prevalent that many chronic childhood diseases, such as autism, pediatric cancers, and type 1 diabetes, are an important cause of neonatal mortality, children morbidity, and long-term disability [1, 5]. Therefore, they represent an important public health and epidemiological problem.

CAs can be isolated or present in a characteristic pattern affecting one or more organ systems.

The overall prevalence of most major CAs does not vary much across ethnic groups [6, 7]. However, the risk for different types of anomalies is variable and may be related to genetic susceptibilities and also to cultural and social differences that can influence exposures (e.g., neural tube defects due to a dietary deficiency of folic acid) [6, 7]. The prevalence of most major birth defects over time has remained constant, but some have shown a significant increase such as gastroschisis [6, 7].

The etiology of CAs is complex. CAs can be the result of genetic factors, environmental factors, or a combination of both [8, 9], although the underlying etiology often remains unknown. It is estimated that genetic factors represent an important cause of CAs and may result from different genetic mechanisms: the most common are aneuploidies, deletions, and duplications of DNA segments (collectively known as CNV), and single gene disorders [8, 9]. Some disorders have an epigenetic basis; genes can be silenced or activated by modifications that may depend on the parent of origin or other influences [4].

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 syndrome, of chromosomal or monogenic etiology.

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

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 epidemiology and etiology of CAs.

The following chapters give an overview of the conventional genetic diagnostic approach and the use of new genomic technologies in the prenatal genetic diagnosis of CAs.
