**3.1. Autosomal dominant inheritance**

Screening and diagnosis limitations for trisomy 13 lead to underdiagnosis of this aneuploidy. Genetic counseling should bring into discussion the viable fetuses in the second trimester (60% of the cases), when life expectancy is very hard to predict and there is no longer the alternative to terminate the pregnancy. It is crucial to inform the parents on the neonatal procedures for resuscitation, possibilities to correct certain defects so that the couple is prepared

For trisomy 18, only 10% of the neonates survive longer than 1 year. Diagnosing this trisomy though genetic testing is essential for decision-making during the neonatal life, where critical

Trisomy 21 has a life expectancy of almost 60 years. Following up, the patient asks for collaborations with multiple medical specialties: cardiological, ENT, ophthalmology, endocrinology, to assess possible complications. During their pediatric life, other interventions are generally symptomatic and similar to their euploid peers [22]. The parents must be prepared though through genetic counseling for the possible difficulties due to motor and cognitive delay. Support in the patient's lifestyle can also come from nongovernmental associations and patient support groups, e.g., Down Syndrome International (https://ds-int.org/

Very often, genetic congenital anomalies are part of the clinical presentation of monogenic diseases; 7.5% of isolated or syndromic congenital anomalies are caused by monogenic disorders. Congenital anomalies can become obvious prenatally or at birth, and at times, they are noticeable only in later development, but in all cases, it happens between conception and birth. The diagnosis of a monogenic disease is often established based on a conclusive family history, clinical examination, and pedigree pattern and confirmed through genetic testing.

With a known diagnosis, the risk of recurrence will be estimated according to the inheritance pattern of the disease. When definite diagnosis is not available, all attempts should be made to associate the clinical picture with a specific disease. If successful, precise genetic counseling can be offered. Situations when diagnosis cannot be demonstrated before birth are difficult to manage—the counselor will advise the couple when there is a lack of crucial medical

Should screening identify congenital anomalies during intrauterine life, couples will be faced with a pressing situation, as anomaly finding does not necessarily imply certain diagnosis. In this case, establishing the diagnosis should be aimed for whenever possible, as the first step

There are situations with a known diagnosis and known disease-causing mutation that allow prenatal diagnosis testing. Prenatal invasive diagnosis for monogenic disease running in the family, depending on its severity, should and will be recommended. If diagnosis can be readily

emergency interventions and choosing invasive treatments are often required [21].

to face the trauma of having a child with lethal defect [20].

448 Congenital Anomalies - From the Embryo to the Neonate

**3. Congenital anomalies in monogenic diseases**

down-syndrome-your-country).

information.

in genetic counseling.

An autosomal dominant disease is a condition expressed in both heterozygous, carrying one copy, and homozygous individuals, carrying two copies one from each parent. The disease is caused by a single gene defect located on an autosome. The affected individuals are usually heterozygous, and the homozygous genotype is associated with more severe features or can be lethal. Females and males exhibit the trait in approximately equal proportions and severity of clinical signs is similar between the two sexes. Both sexes are equally likely to transmit the mutation to their offspring. Mostly, the affected offsprings are descendants of an affected heterozygous and a normal parent. On average, half of the children will be heterozygous and express the disease and half will not. Rarely, homozygous are seen in autosomal dominant diseases. This status can be due to a higher frequency of a gene with mild effects, late onset (e.g. Huntington disease) or when both parents are affected (e.g. achondroplasia). Unusually, an affected homozygous parent will transmit the disease to all of his children. On the pedigree, a vertical transmission pattern is observed (**Figure 4**), and the disease phenotype is usually seen in one generation after another. The disease does not skip generations: if an individual has an autosomal disease, in most of the cases, one parent must also have it [1, 2].

Frequently, autosomal dominant disorders involve different organs and systems of the body; however, dominant conditions affecting one organ have been described (e.g., congenital cataract). The capacity of a single gene to affect unrelated organs is called *pleiotropy* (e.g., Marfan syndrome can affect the skeletal, ocular, and cardiovascular systems; some affected individuals have all features, whereas others may have almost none). In addition, the clinical features in autosomal dominant disorders can show remarkable variation between patients, even between the members of the same family. This difference between individuals is referred to as *variable expressivity* (e.g., in autosomal dominant polycystic kidney disease, some affected individuals develop renal failure in early adulthood, whereas others have just a few renal cysts that do not significantly influence renal function). Occasionally, the heterozygous and homozygous individuals express identical phenotype (complete dominance) [2, 23].

Sometimes, a dominant mutation is inherited, but the condition it determines is not expressed. In these cases, the gene has *reduced (incomplete)penetrance.* The term penetrance is used in monogenic inheritance to indicate the probability of a gene to influence the phenotype. A number of autosomal dominant diseases show an incomplete penetrance (e.g., polydactyly), meaning that a person has the mutation but shows no evidence of a disease. A gene is *completely penetrant* if each individual who inherited the mutation expresses clinical features (e.g., neurofibromatosis type I) [3].

**3.2. Autosomal recessive inheritance**

**Figure 5.** Autosomal recessive inheritance.

An autosomal recessive disease is a condition expressed only in homozygous individuals with both mutant alleles. The parents of such homozygotes must be at least heterozygous for the disease allele and are usually referred to as carriers for that disorder (**Figure 5**). In most cases, the *loss-of-function* mutation is a process in which mutant allele reduces or removes the function of an enzyme. In the heterozygous state, the normal allele can compensate the mutant one, and in homozygotes or compound homozygotes with both mutant alleles, the disease occurs [1, 2, 4]. When two carrier parents of the mutant allele are matting, there is a 50% chance for each of them to transmit either the wild-type or the mutant allele. Thus, each of them has a 50% chance to transmit the mutant allele and further 25% of offspring may be homozygous affected. This also means that 50% of the cases the offspring will get one wild-type allele and one mutant allele, resulting in a carrier. If a parent is affected by a recessive disorder and the other is heterozygous there is a 50% chance that the disorder will be transmitted to children, depending on which allele the partner contributes with. All children are carriers when a parent is affected

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by an autosomal recessive disorder and the other is homozygous wild-type [1, 4].

**Figure 4.** Autosomal dominant inheritance.

Often, known autosomal dominant conditions are seen in a person without an affected parent. The condition seems to be isolated and no clinical features are detected among other family members. In these cases, the disease can be attributed to a "*de novo" mutation* and the recurrence risk for siblings is very low. The mutation is found only in a gamete and the mutated gene is transmitted by one of the healthy parents. The percent of cases caused by de novo mutations is influenced by the severity of clinical features or the capability of reproduction. Osteogenesis imperfecta type II is exclusively caused by new mutations, the condition being perinatally lethal. Also, more than 80% of cases with achondroplasia are due to new mutations, and the proportion is significantly lower in polycystic kidney disease. In this case, it is important to know the family history to distinguish isolated cases and rule out incomplete penetrance or variation in expression. The detection of a specific mutation in a proband allows direct testing of the parents to exclude a disease with expression variability. Also, the detection of a specific mutation can help predict the severity of clinical features in some diseases [24].

*Germline mosaicism* is another mechanism documented in a number of autosomal dominant diseases such as tuberous sclerosis or osteogenesis imperfecta. Germline mosaicism, also known as gonadal mosaicism, is a condition in which the precursor (germ line) cells to egg and sperm cells are a mixture (mosaic) of two or more genetically different cell lines [1, 2]. The parents do not exhibit any clinical features because the somatic cells are not affected; only a proportion of eggs or sperm cells are carriers of the mutation. Two or more children are affected when there is no family history of disease. This condition is associated with increased recurrence risk for future offspring of a mosaic parent. Because mutation is a rare event, it is unlikely that this would be due to multiple mutations in the same family.

### **3.2. Autosomal recessive inheritance**

An autosomal recessive disease is a condition expressed only in homozygous individuals with both mutant alleles. The parents of such homozygotes must be at least heterozygous for the disease allele and are usually referred to as carriers for that disorder (**Figure 5**). In most cases, the *loss-of-function* mutation is a process in which mutant allele reduces or removes the function of an enzyme. In the heterozygous state, the normal allele can compensate the mutant one, and in homozygotes or compound homozygotes with both mutant alleles, the disease occurs [1, 2, 4].

When two carrier parents of the mutant allele are matting, there is a 50% chance for each of them to transmit either the wild-type or the mutant allele. Thus, each of them has a 50% chance to transmit the mutant allele and further 25% of offspring may be homozygous affected. This also means that 50% of the cases the offspring will get one wild-type allele and one mutant allele, resulting in a carrier. If a parent is affected by a recessive disorder and the other is heterozygous there is a 50% chance that the disorder will be transmitted to children, depending on which allele the partner contributes with. All children are carriers when a parent is affected by an autosomal recessive disorder and the other is homozygous wild-type [1, 4].

**Figure 5.** Autosomal recessive inheritance.

Often, known autosomal dominant conditions are seen in a person without an affected parent. The condition seems to be isolated and no clinical features are detected among other family members. In these cases, the disease can be attributed to a "*de novo" mutation* and the recurrence risk for siblings is very low. The mutation is found only in a gamete and the mutated gene is transmitted by one of the healthy parents. The percent of cases caused by de novo mutations is influenced by the severity of clinical features or the capability of reproduction. Osteogenesis imperfecta type II is exclusively caused by new mutations, the condition being perinatally lethal. Also, more than 80% of cases with achondroplasia are due to new mutations, and the proportion is significantly lower in polycystic kidney disease. In this case, it is important to know the family history to distinguish isolated cases and rule out incomplete penetrance or variation in expression. The detection of a specific mutation in a proband allows direct testing of the parents to exclude a disease with expression variability. Also, the detection of a specific mutation can help predict the severity of clinical features in some diseases [24].

**Figure 4.** Autosomal dominant inheritance.

450 Congenital Anomalies - From the Embryo to the Neonate

*Germline mosaicism* is another mechanism documented in a number of autosomal dominant diseases such as tuberous sclerosis or osteogenesis imperfecta. Germline mosaicism, also known as gonadal mosaicism, is a condition in which the precursor (germ line) cells to egg and sperm cells are a mixture (mosaic) of two or more genetically different cell lines [1, 2]. The parents do not exhibit any clinical features because the somatic cells are not affected; only a proportion of eggs or sperm cells are carriers of the mutation. Two or more children are affected when there is no family history of disease. This condition is associated with increased recurrence risk for future offspring of a mosaic parent. Because mutation is a rare event, it is

unlikely that this would be due to multiple mutations in the same family.

*Consanguinity* is referred to as a couple who have at least a common ancestor, meaning that they are relatives. Finding out that an individual with a genetic disorder is the result of a consanguineous couple is strong evidence for a recessive condition, although not certainty, because there is a greater chance that the parents would have inherited the mutant allele from their common ancestor and passed it down, than the possibility of finding a similar mutation in two unrelated individuals in the general population. In fact, this is true for very rare mutations (e.g., alkaptonuria or xeroderma pigmentosum). In contrast for common autosomal recessive disorders (e.g., cystic fibrosis), the incidence in general population is not significantly lower than in consanguineous marriages. Meaning that the rarer the mutation is in the general population, the more likely that the parents are related (consanguinity) [5].

*X-inactivation* is a normal process, which appears in the early development of the embryo. The result is that most of the genes on one of the two X chromosomes in females are inactivated in each cell, ensuring the fact that, similar to males, females have only one functional X chromosome. One of the two chromosomes is randomly inactivated, meaning that approximately half of the cells in females have a functional X chromosome of maternal origin and the other half have the paternal one functional. This process interferes with both dominant and reces-

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X-linked dominant inheritance is caused by a dominant mutant allele located on the X chromosome. Hemizygous males and both homozygous and heterozygous females are affected. Males are more likely to be severely affected given the fact that in females one of the X chromosomes will be inactivated (X-inactivation), unless the females are homozygous for that

Affected heterozygote offsprings of both sexes have a 50% chance to inherit the mutant allele from an affected mother, which is similar in the autosomal dominant inheritance too (**Figure 6**). The difference between the autosomal and X-linked dominant inheritance refers to affected males. All daughters of an affected male will also be affected by inheriting the X chromosome with the mutant allele, whereas male offsprings will inherit the Y chromosome, thus avoiding the disorder. Affected females are twice more frequent than affected males, although females tend to have milder phenotypic manifestations. One example of an X-linked dominant inheri-

In some cases, affected males with an X-linked dominant disorder are rarely seen, for example, Rett syndrome and incontinentia pigmenti. This is due to the fact that the presence of the mutant allele in male hemizygotes will result in an early embryonic development stop. In other cases, it seems that only females are affected because males are "speared." An example of a disorder that spares male hemizygotes is X-linked females—limited epilepsy and cognitive impairment. Females appear to be healthy at birth, yet they develop the affection from the second year of life, while males are unaffected their whole life. This disorder is caused by a loss of functional mechanism in the protocadherin gene 19, which is expressed in the neurons. The explanation for this particular case would be that random X-inactivation makes a mosaic expression of this gene in the cells of the central nervous system, which disrupts communications between neurons. In males, the brain is spared this miscommunication between neurons

by seemingly a different protocadherin, which compensates the loss of the first [6].

X-linked recessive inheritance is caused by a recessive mutant gene located on the X chromosome. Almost all affected individuals are males (hemizygotes), while homozygotes affected females are rarely seen. The clinical features seen in females are mainly due to non-random

All daughters of an affected male (hemizygous) will be carriers (heterozygotes) for a specific disorder, whereas the sons will inherit the Y chromosomes from the father and thus will be

sive X-linked inheritance as detailed below [5].

tance disorder is the hypophosphatemic rickets [1, 2, 4].

*3.3.1. X-linked dominant inheritance*

*3.3.2. X-linked recessive inheritance*

X-inactivation [4].

allele.

There are specific recessive disorders for which it is not uncommon that two affected individuals will have children together. Such is the case for individuals with deafness or visual impairment who will benefit from the same social facilities or will be educated together. If the disorder is caused by the same mutation, then all their children would be affected; however, there are studies that show that normal children are born from these couples. The most common explanation is that the parents are homozygous for different genes, both causing deafness, and so the children are heterozygous for both mutations, also known as double heterozygote. This type of genetic heterogeneity is called *locus heterogeneity.* Heterogeneity can also be found in the same locus, as it would be the case of an affected individual who is heterozygote for both alleles, making him/her a *compound heterozygote*. Most affected individuals with recessive autosomal inherited disorders are compound heterozygotes, unless that specific mutation is rather common in the general population (as is the case with cystic fibrosis), or he/she is the result of a consanguinity marriage [1].

Another method of assessing recurrence risk is by calculating the genotype frequency, knowing the allele frequency. This is not as straightforward as it would seem because there is the matter of allele distribution in heterozygotes and homozygotes. This can be done by using the *Hardy-Weinberg Law*, but the population used on has to meet some criteria such as: (a) the population is large and the mattings are random; (b) there is no significant rate of new mutations; (c) there is no selection for any genotype; and (d) there is no significant migration disturbing the endogenous population allele frequency [6].

The presence of both homologous from a pair or chromosomal regions in an offspring coming from the same parent is called *uniparental disomy*. The uniparental disomy can be caused by an error in meiosis resulting in two different chromosomes coming from the same parent, which is called heterodisomy, or by an error in meiosis II, which will result in identical chromosomes transmitted from the same parent called isodisomy. This abnormality has been reported to be a rare cause for cystic fibrosis, in families where only one parent is heterozygote and the offspring takes both homologous chromosomes with the mutant allele from that parent [1, 4].

### **3.3. Sex-linked inheritance**

This type of inheritance is linked to the genes found on the sex chromosomes. Inheritance patterns for the genes found on X chromosome relates to X-linked inheritance, while for the genes located on Y chromosomes, it is called holandric or Y-linked inheritance. The genes positioned on the X and Y chromosomes are unequally transmitted to males and females.

*X-inactivation* is a normal process, which appears in the early development of the embryo. The result is that most of the genes on one of the two X chromosomes in females are inactivated in each cell, ensuring the fact that, similar to males, females have only one functional X chromosome. One of the two chromosomes is randomly inactivated, meaning that approximately half of the cells in females have a functional X chromosome of maternal origin and the other half have the paternal one functional. This process interferes with both dominant and recessive X-linked inheritance as detailed below [5].
