*3.3.1. X-linked dominant inheritance*

*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].

fibrosis), or he/she is the result of a consanguinity marriage [1].

452 Congenital Anomalies - From the Embryo to the Neonate

disturbing the endogenous population allele frequency [6].

**3.3. Sex-linked inheritance**

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

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

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].

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-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 allele.

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

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].

#### *3.3.2. X-linked recessive inheritance*

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 X-inactivation [4].

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

**Figure 6.** X-linked dominant inheritance.

unaffected by the disorder. For a female carrying the mutation, there is a 50% chance to transmit the mutant X chromosome to the offspring, as a result 50% of the daughters will be carriers and 50% of the sons will be affected (**Figure 7**). For a female to be affected means to inherit the mutant allele from each parent, which is very unlikely to happen, or another option is the presence of only one X chromosome (monosomy X) on which the mutation is present, making her a hemizygous for the allele, like in the case of males. A commonly known X-linked recessive disorder is hemophilia A caused by deficiency of factor VIII, a protein involved in clotting [1, 2, 6].

*3.3.3. Y-linked inheritance*

**Figure 7.** X-linked recessive inheritance.

male descendants and none of his female ones.

Y-linked inheritance also known as holandric inheritance is caused by genes located on the Y chromosome. This is a rather straightforward type of inheritance as only males have Y chromosome, meaning that a male will transmit the mutant allele and thus the disorder to all his

Prenatal Genetic Counseling in Congenital Anomalies http://dx.doi.org/10.5772/intechopen.74394 455

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

Congenital anomalies, also referred to as congenital abnormalities, congenital malformations, congenital disorders, or birth defects, are conditions of prenatal origin that describe developmental

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

equina), with an incidence of approximately 1–8% in newborns [25].

Sometimes, the females can express the phenotype. The most common situation is represented by a carrier female showing phenotypic features, phenomenon known as *manifesting heterozygote.* This manifestation is due to X-inactivation, which is not random anymore; rather, it has become unbalanced or skewed. The skewed X-inactivation can be both advantageous when the inactivated X chromosome in all or most cell lines and tissues is the one with the mutation and deleterious when inactivation occurs on the X chromosome containing the wild-type allele. This unbalance can be created through chance alone by selecting mostly one of the X chromosomes, rather than the other, or through different mechanisms like cytogenetic abnormalities (translocation) or removal of the cells containing the mutant allele [6].

The *germline mosaicism (gonadal mosaicism)* is an important mechanism in assessment of X-linked recessive inheritance risk and it was also seen in autosomal dominant inheritance. Because both male and female gametogenesis can be affected, it should be taken into account when the recurrence risk is assessed in apparently sporadically appeared X-linked disorders like Duchenne muscular dystrophy [1].

**Figure 7.** X-linked recessive inheritance.

#### *3.3.3. Y-linked inheritance*

unaffected by the disorder. For a female carrying the mutation, there is a 50% chance to transmit the mutant X chromosome to the offspring, as a result 50% of the daughters will be carriers and 50% of the sons will be affected (**Figure 7**). For a female to be affected means to inherit the mutant allele from each parent, which is very unlikely to happen, or another option is the presence of only one X chromosome (monosomy X) on which the mutation is present, making her a hemizygous for the allele, like in the case of males. A commonly known X-linked recessive disorder is hemophilia A caused by deficiency of factor VIII, a protein involved in clotting [1, 2, 6].

Sometimes, the females can express the phenotype. The most common situation is represented by a carrier female showing phenotypic features, phenomenon known as *manifesting heterozygote.* This manifestation is due to X-inactivation, which is not random anymore; rather, it has become unbalanced or skewed. The skewed X-inactivation can be both advantageous when the inactivated X chromosome in all or most cell lines and tissues is the one with the mutation and deleterious when inactivation occurs on the X chromosome containing the wild-type allele. This unbalance can be created through chance alone by selecting mostly one of the X chromosomes, rather than the other, or through different mechanisms like cytogenetic abnor-

The *germline mosaicism (gonadal mosaicism)* is an important mechanism in assessment of X-linked recessive inheritance risk and it was also seen in autosomal dominant inheritance. Because both male and female gametogenesis can be affected, it should be taken into account when the recurrence risk is assessed in apparently sporadically appeared X-linked disorders

malities (translocation) or removal of the cells containing the mutant allele [6].

like Duchenne muscular dystrophy [1].

**Figure 6.** X-linked dominant inheritance.

454 Congenital Anomalies - From the Embryo to the Neonate

Y-linked inheritance also known as holandric inheritance is caused by genes located on the Y chromosome. This is a rather straightforward type of inheritance as only males have Y chromosome, meaning that a male will transmit the mutant allele and thus the disorder to all his male descendants and none of his female ones.
