Medical Genetics - V. M. Zaporozhan 2005

Clinical-Genealogical Method
Characteristics of Pedigrees with Various Inheritance Patterns
Sex-Linked Inheritance

This is the Inheritance of Traits determined by genes located on the sex Chromosomes. It includes X-linked dominant, X-linked recessive, and Y-linked Patterns of inheritance. All types of Sex-Linked Inheritance are characterized by varying frequencies of affected males and females in a pedigree.

X-Linked Inheritance

The Features of X-linked inheritance are determined by the following:

1. Females have two X chromosomes, whereas males have an X and a Y chromosome. Since many genes on the X and Y chromosomes are non-homologous, the genes on the X chromosome in males lack a counterpart (a hemizygous state).

2. Daughters and sons inherit an X chromosome from their mother, but only daughters inherit one from their father; accordingly, X-linked disorders are never transmitted from father to son.

Genes localized on the X chromosome can be either dominant or recessive.

X-linked recessive inheritance. The pathological Gene is designated as X^a, and the normal allele as X^A. The genotype of a healthy female is designated as X^AX^A or X^AX^a (a heterozygous carrier), and that of a healthy male as X^A. The genotype of an affected female is X^aX^a, and that of an affected male is X^aY (or X^A depending on the context, but keeping the format).

X-linked recessive inheritance (Fig. 4.7) is characterized by the following:

1. Males are predominantly affected (X^aY), because in a hemizygous male, the disease gene will always manifest phenotypically.

2. All children of an affected father are healthy.

3. Affected males transmit the pathological allele to all their daughters, who become heterozygous carriers of the gene.

4. Transmission of the disorder from father to son is never observed, since a son always inherits the Y chromosome from his father.

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Fig. 4.7. Pedigree in X-linked recessive inheritance

5. An affected son inherits the disorder from a healthy mother who is a heterozygous carrier of the pathological gene. In inherited cases, affected boys may have affected brothers and maternal uncles. A son's condition may also be caused by a new mutation in the mother's X chromosome.

6. In a marriage between a carrier female and a healthy male, all daughters are healthy (50% of them are carriers), 50% of the sons are affected, and 50% of the sons are healthy.

7. The birth of an affected daughter is possible in a marriage between a carrier female and an affected male: 50% of daughters are healthy, 50% are carriers, 50% of sons are affected, and 50% are healthy (Fig. 4.8).

Some difficulties may arise during pedigree analysis. In heterozygous gene carriers, the trait may manifest phenotypically due to the preferential inactivation of the X chromosome carrying the normal allele (Barr bodies).

If the X^a gene has a lethal effect, all male fetuses that inherit this gene perish. Heterozygous female carriers are healthy, but half of their male offspring die. As a result, The ratio of female to male offspring in the pedigree will be 2:1.

Sometimes affected males (e.g., in Duchenne muscular dystrophy) leave no offspring because they die before reaching Puberty or are sterile.

X-linked dominant inheritance. The pathological gene is designated as X^A, and the normal allele as X^a. The genotype of a healthy female is designated as X^aX^a, and that of a healthy male as X^aY (or X^A). The genotype of an affected female is X^AX^A or X^AX^a, and that of an affected male is X^AY.

X-linked dominant inheritance (Fig. 4.9) has the following features:

1. Both males and females are affected, but the number of affected females in the pedigree is twice that of males.

2. Children are affected only if one of the parents is affected. Healthy parents have only healthy children.

3. The disease can be traced in every generation.

4. If the mother is heterozygous (X^AX^a), 50% of both daughters and sons inherit the trait.

Fig. 4.8. Pedigree showing two females homozygous for hemophilia. The parents of the females are first cousins (after F. Vogel and A. Motulsky)

5. All daughters and no sons inherit the trait from an affected father, since a son inherits the Y chromosome from his father.

6. Females present with a milder form of the disease because they are more frequently heterozygous (X^AX^a). In hemizygous males (XY), the disease manifests in a more severe form. The dominant gene may be lethal in male embryos. In such cases, all affected individuals in the pedigree are exclusively female (Fig. 4.10).

Y-linked inheritance pattern

The Y chromosome contains genes that control Spermatogenesis, body and limb growth, tooth development, hypertrichosis of the ear rim, and other traits (holandric traits). Since the Y chromosome is transmitted from father to son, pedigrees are characterized by the following features (Fig. 4.11):

1. Only males are affected.

2. All sons inherit the trait from an affected father.

Fig. 4.9. Pedigree for X-linked dominant inheritance

Pathological Mutations affecting spermatogenesis cannot be inherited because affected individuals are sterile. However, transmission of the gene is possible via In vitro Fertilization.

All inheritance patterns discussed above are associated with nuclear DNA mutations.

Fig. 4.10. Pedigree for X-linked inheritance in cases of embryonic lethality of the pathological gene in male embryos (Bloch-Sulzberger syndrome)

Fig. 4.11. Pedigree for Y-linked trait inheritance (hypertrichosis of the ear rim)