**4. Genetic counseling in multifactorial congenital anomalies**

Multifactorial heredity describes a trait whose manifestations are determined by the activity of one or more genes in combination with environmental factors that can trigger, accelerate, or exacerbate the pathological process. Multifactorial diseases present a specific familial disposition, the incidence for close relatives of the affected individual being about 2–4%, unlike diseases determined by the mutations of a single gene (25–50%) [7].

These types of pathologies are classified into two main categories: (1) common diseases of adulthood (coronary disease, hypertension, diabetes, asthma, schizophrenia, etc.), having a prevalence of around 1–5%, and (2) isolated congenital abnormalities of the childhood (e.g. neural tube defects, cleft lip and anterior palate, congenital anomalies of the heart, varus equina), with an incidence of approximately 1–8% in newborns [25].

Congenital anomalies, also referred to as congenital abnormalities, congenital malformations, congenital disorders, or birth defects, are conditions of prenatal origin that describe developmental disorders of the embryo and fetus, potentially impacting its health and development [26]. There is a wide array of anomalies including structural and functional conditions that can fall under these headings [3].

• The presence of a more severe condition in the proband. If the proband has a unilateral oral cleft, the risk to siblings is 1.9%, and if the proband has bilateral oral cleft, the risk rises to

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• The presence in the family of several affected individuals. In the case of labia, if two siblings are affected, the risk for the next birth is 10%; if a parent and child are affected, then

• Sex of the proband. The risk increases if in the family there are sick individuals of a certain sex at which the illness is normally less frequent (i.e., developmental dysplasia of the hip in

• Consanguinity increases the risk of recurrence because the risk genes are inherited from

If for certain isolated congenital anomalies there is no information on the empirical risk in a given population, the risks may be recalculated based on the population frequency and the

*Recurrence risks per pathology*. Regarding *congenital anomalies of the heart*, the recurrence risk is greater on the horizontal line (brotherhood) than on the vertical line for first-degree relatives and it revolves around 2–4%, whereas for second-degree relatives, the risk is reduced, becoming similar to that of the general population [35]. On the other hand, though, if the affected parent is the mother, the recurrence risk is significantly higher than the one for which the

*Cleft lip* when associated or not with anterior palate represents the most common facial congenital anomaly, being present in over 20% of the cases and also having a positive family

At birth, the fact that the child has an affected mother and that she has another affected child increases the prevalence. The recurrence risk for patients that have first-degree relatives with this disease is 32 times greater than in the general population for cleft lip and anterior palate and 56 times greater for anterior palate alone, even though patients with cleft lip have a high

In regard to *neural tube defects*, recent studies have pointed that if the proband would be the first affected child in the family then the recurrence risk for the following children would be 3.15%, whereas for the second affected sibling, the risk for recurrence would be around 10–11.76%. Some studies also showed that the risk is higher for female children and for the

*Congenital hip dislocation* has a 5% recurrence risk if an affected sibling is already present. An increased risk of male probing according to sex ratio (8 males per 1 affected female) is encoun-

*Varus equina* seems to be twice as frequent in girls as in boys, while in families that have one child with this condition, the occurrence risk for the following children is 30 times higher than

severity of the condition, as well as the number of affected individuals.

6.6%.

both sides.

history.

the risk for another affected child is 14%.

father would have been the carrier of the anomaly.

familial recurrence of almost 4%.

first and last siblings of a mother.

tered in people affected by this congenital anomaly.

that of the general population being approximately 7.3%.

boys and pyloric stenosis in girls).

Congenital anomalies are affecting 1–6% of pregnancies worldwide, making them a leading cause of morbidity and mortality in early life [8, 9, 27, 28]. In high-income countries, a quarter of the infant deaths is due to these anomalies [10, 29, 30]. Mortality in children under 5 years old escalates to 3.3 million [28].

These anomalies can occur in isolation (isolated congenital anomalies) or as a group of defects (multiple congenital anomalies). However, there is no generally accepted system of classification, or even an agreed definition of what constitutes a congenital anomaly [3].

Improvements in the sensitivity and availability of prenatal screening have helped decrease the number of children born with congenital anomalies [8, 31]. Even so, when the event arises, the diagnosis and the discussions around pregnancy termination create significant emotional distress [32]. Moreover, parents who have lost a child to a congenital anomaly or families with a preexisting condition will be very concerned about the risk of recurrence in future pregnancies [11].

The role of genetic counseling is to provide guidance and support to the families being affected by these conditions [12, 24], yet the etiology of most congenital anomalies is multifactorial or unknown [33] and so an exact evaluation of the recurrence risk is hard to make for most anomaly groups and subtypes. There are a few population-based studies that offer some information concerning the recurrence risk [13, 14, 34]. All three studies conducted in the 1990s found that a congenital anomaly has twice the risk of occurrence in a future pregnancy if it has already been present, and the risk rises 5- to 12-fold if the same anomaly is present in the subsequent pregnancy [13, 14, 34]. These studies have also limitations, due to small sample size, lack or outdated classification, rendering them less useful. There is also more accurate data available in a recent article [3] that shows that for similar anomalies the recurrence risk for isolated congenital anomalies is 20-fold higher, while for dissimilar anomalies, the recurrence risk is 1.3-fold higher. Also, it was concluded in the article that the absolute recurrence risk varies between 1 in 20 and 1 in 30 [3].

*General recurrence risk.* Under these conditions, a number of general principles must be respected for genetic counseling. The empirical risk represents a medium risk for the respective disease in the population of which the proband (index case) is, and so it is possible that in the studied family the average risk is not the same as the real risk.

The overall empirical risk of recurrent fracture or progression for isolated congenital malformations with a frequency of 1–1000 newborns is about 2.5% for common diseases; at a frequency of 1–100, the risk is about 10%.

The risk of recurrence of the condition is influenced by a number of factors:

• The degree of kinship with the proband (index case). The risk of recurrence to first-degree relatives is much higher than for other people in the family; for example, the descendants and siblings of a proband with oral cleft have a risk of 3.15 and 2.79%, respectively, and the second- and third-degree relatives have much lower risks, 0.47 and 0.27%, respectively.

• The presence of a more severe condition in the proband. If the proband has a unilateral oral cleft, the risk to siblings is 1.9%, and if the proband has bilateral oral cleft, the risk rises to 6.6%.

disorders of the embryo and fetus, potentially impacting its health and development [26]. There is a wide array of anomalies including structural and functional conditions that can fall

Congenital anomalies are affecting 1–6% of pregnancies worldwide, making them a leading cause of morbidity and mortality in early life [8, 9, 27, 28]. In high-income countries, a quarter of the infant deaths is due to these anomalies [10, 29, 30]. Mortality in children under 5 years

These anomalies can occur in isolation (isolated congenital anomalies) or as a group of defects (multiple congenital anomalies). However, there is no generally accepted system of classifica-

Improvements in the sensitivity and availability of prenatal screening have helped decrease the number of children born with congenital anomalies [8, 31]. Even so, when the event arises, the diagnosis and the discussions around pregnancy termination create significant emotional distress [32]. Moreover, parents who have lost a child to a congenital anomaly or families with a preexisting condition will be very concerned about the risk of recurrence in future pregnancies [11].

The role of genetic counseling is to provide guidance and support to the families being affected by these conditions [12, 24], yet the etiology of most congenital anomalies is multifactorial or unknown [33] and so an exact evaluation of the recurrence risk is hard to make for most anomaly groups and subtypes. There are a few population-based studies that offer some information concerning the recurrence risk [13, 14, 34]. All three studies conducted in the 1990s found that a congenital anomaly has twice the risk of occurrence in a future pregnancy if it has already been present, and the risk rises 5- to 12-fold if the same anomaly is present in the subsequent pregnancy [13, 14, 34]. These studies have also limitations, due to small sample size, lack or outdated classification, rendering them less useful. There is also more accurate data available in a recent article [3] that shows that for similar anomalies the recurrence risk for isolated congenital anomalies is 20-fold higher, while for dissimilar anomalies, the recurrence risk is 1.3-fold higher. Also, it was concluded in the article that the absolute

*General recurrence risk.* Under these conditions, a number of general principles must be respected for genetic counseling. The empirical risk represents a medium risk for the respective disease in the population of which the proband (index case) is, and so it is possible that in

The overall empirical risk of recurrent fracture or progression for isolated congenital malformations with a frequency of 1–1000 newborns is about 2.5% for common diseases; at a

• The degree of kinship with the proband (index case). The risk of recurrence to first-degree relatives is much higher than for other people in the family; for example, the descendants and siblings of a proband with oral cleft have a risk of 3.15 and 2.79%, respectively, and the second- and third-degree relatives have much lower risks, 0.47 and 0.27%, respectively.

tion, or even an agreed definition of what constitutes a congenital anomaly [3].

recurrence risk varies between 1 in 20 and 1 in 30 [3].

frequency of 1–100, the risk is about 10%.

the studied family the average risk is not the same as the real risk.

The risk of recurrence of the condition is influenced by a number of factors:

under these headings [3].

old escalates to 3.3 million [28].

456 Congenital Anomalies - From the Embryo to the Neonate


If for certain isolated congenital anomalies there is no information on the empirical risk in a given population, the risks may be recalculated based on the population frequency and the severity of the condition, as well as the number of affected individuals.

*Recurrence risks per pathology*. Regarding *congenital anomalies of the heart*, the recurrence risk is greater on the horizontal line (brotherhood) than on the vertical line for first-degree relatives and it revolves around 2–4%, whereas for second-degree relatives, the risk is reduced, becoming similar to that of the general population [35]. On the other hand, though, if the affected parent is the mother, the recurrence risk is significantly higher than the one for which the father would have been the carrier of the anomaly.

*Cleft lip* when associated or not with anterior palate represents the most common facial congenital anomaly, being present in over 20% of the cases and also having a positive family history.

At birth, the fact that the child has an affected mother and that she has another affected child increases the prevalence. The recurrence risk for patients that have first-degree relatives with this disease is 32 times greater than in the general population for cleft lip and anterior palate and 56 times greater for anterior palate alone, even though patients with cleft lip have a high familial recurrence of almost 4%.

In regard to *neural tube defects*, recent studies have pointed that if the proband would be the first affected child in the family then the recurrence risk for the following children would be 3.15%, whereas for the second affected sibling, the risk for recurrence would be around 10–11.76%. Some studies also showed that the risk is higher for female children and for the first and last siblings of a mother.

*Congenital hip dislocation* has a 5% recurrence risk if an affected sibling is already present. An increased risk of male probing according to sex ratio (8 males per 1 affected female) is encountered in people affected by this congenital anomaly.

*Varus equina* seems to be twice as frequent in girls as in boys, while in families that have one child with this condition, the occurrence risk for the following children is 30 times higher than that of the general population being approximately 7.3%.

The indirect setting, based on family history, of an increased individual risk of the disease will allow for the direct determination by molecular tests of genetic risk factors, possibly specific medical actions of early diagnosis.

*Biopsy procedures and genetic analysis technique.* Genetic testing can be performed using biological samples obtained by one of the following: polar body, cleavage-stage embryo, or blasto-

Prenatal Genetic Counseling in Congenital Anomalies http://dx.doi.org/10.5772/intechopen.74394 459

Polar body biopsy. First and second polar bodies are haploid cells produced in the first and, respectively, second meiotic division of oogenesis. The genetic evaluation of both polar bodies is required to precisely establish the genetic status of the oocyte. Because polar bodies are not a part of the zygote, this technique is mainly performed in some countries where embryo biopsy is unauthorized by law. Polar body analysis only provides data about mutations or aneuploidies of maternal origins. The chromosome abnormalities occurring postmeiotically (e.g., mosaicism and polyploidy), limited amount of genetic material, and doubling the number of samples for analysis have made the need to perform this type of biopsy questionable [36, 21]. Cleavage-stage embryo biopsy. Cleavage-stage biopsy is usually performed on day 3 when early embryo consists of approximately 6–10 cells. At this stage, the cells are still totipotent and are not yet adhering to one another, allowing the extraction of a single blastomere for genetic testing. Limited amount of genetic material and high rates of mosaicism observed in early embryos can lead to misdiagnosis at this stage. The biopsy of two blastomeres was associated with deleterious effects on embryo development and is recommended to be avoided [22, 37]. Blastocyst biopsy. The embryo reaches the blastocyst stage on day 5 or 6 after fertilization. The blastocyst contains about 100 cells and comprises the outer trophectoderm and inner cell mass. During blastocyst biopsy, 5–10 trophectoderm cells are retrieved; thus, more material for genetic diagnosis is available. The ethical and safety considerations related to early embryo biopsy are overcome somewhat because the trophectoderm cells will differentiate into trophoblast cells and further go on to form placenta and other extraembryonic tissues, and not participate to form the embryo [15, 23]. Recent studies showed that this type of biopsy has no effect on reproductive capacity of a blastocyst [16, 24]. However, only about 40–50% of preimplantation embryos will reach this stage in vitro. Because the time to obtain a genetic diagnosis is very limited to perform a fresh embryo transfer, mostly frozen embryo transfer is performed after vitrification [15, 16, 36]. *Genetic analysis techniques.* After the biological material is available for biopsy, the genetic analysis can be performed. The evaluation is based on only a single cell or very limited genetic material. For fresh embryo transfer, the genetic diagnosis must be done within 24–36 h. The single-gene mutations are detected using molecular genetic methods (PCR, PCR-multiplex, RTqPCR, whole genome amplification, or even next-generation sequencing) and chromosomal abnormalities (e.g., translocation and aneuploidies) by cytogenetic techniques (FISH,

The embryo testing using genetic methods with the aim to detect *de novo* chromosomal aneuploidies is known as preimplantation genetic screening (PGS) [26]. PGS analyzes whether a single cell or a small number of cells biopsied from a preimplantation embryo is euploid before transferring it to the uterus. PGS is not PGD, being mainly offered to couples with advanced maternal age, recurrent implantation failure or recurrent miscarriages, and other conditions associated with high risk for aneuploid embryos in order to increase the success rate of IVF (~30%). PGS can be performed using FISH, multiplex quantitative PCR, or chro-

cyst biopsy [15, 16].

array CGH, and SNP array) [16, 25].

mosomal microarrays [16, 27, 28].

To summarize, genetic counseling in isolated congenital anomalies relies on information gathered from population-based studies, on new and future discoveries related to the etiology of these disorders, and other factors such as the degree of kinship with the proband, presence of a more severe condition, more than one individual affected in the same family, or consanguinity for calculating the recurrence risk for the respective condition.

Genetic counseling is about guidance and support for the patient and the patient's family, so a great deal of attention must also be directed toward careful wording when explaining the risk and decisions that need to be made.
