Medical Genetics - V. M. Zaporozhan 2005

Etiology of Hereditary Diseases
Non-Mendelian Inheritance in Humans
Uniparental Diploidy, Uniparental Disomy, and Isodisomy

Uniparental diploidy is the inheritance of a diploid set of Chromosomes from only one parent. Due to Genomic Imprinting, such embryos are non-viable. If an embryo inherits a paternal diploid set of chromosomes, it results in The formation of a Hydatidiform Mole (an empty gestational sac). This refers to an embryo in which the embryoblast fails to develop, and only extraembryonic membranes are formed. Cystic degeneration of the chorionic villi is observed, and the embryos are aborted. There is a risk of developing a malignant chorionic tumor, Choriocarcinoma. All 46 chromosomes of such an embryo are of paternal origin and homozygous for all genes. It is believed that such embryos are formed As a result of the degeneration of the oocyte pronucleus after Fertilization by a spermatozoon. Subsequently, the paternal chromosomes duplicate, and The Cell restores its diploid chromosome set (Fig. 2.17).

Ovarian teratomas, conversely, have a maternal diploid chromosome set. They consist of embryonic Tissues and lack extraembryonic Organs (chorion, Placenta, etc.).

Uniparental disomy is the inheritance of two homologous chromosomes from a single parent. This is widely considered to result from the loss of a single chromosome in a zygote with an initially trisomic set (trisomy rescue). Non-disjunction of chromosomes occurs During the first meiotic division in one of the parents. Consequently, the zygote receives an extra chromosome from one parent, becoming trisomic. Later, one of the chromosomes is lost during mitotic division of the zygote, and the embryo restores a normal chromosome set. However, the sole chromosome contributed by one parent may be lost, leaving behind the two chromosomes inherited from the other parent (uniparental disomy).

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Fig. 2.17. Formation of a diploid zygotic Nucleus containing two sets of paternal chromosomes: a — the oocyte is fertilized by a single spermatozoon, and the oocyte nucleus is lost; b — the male pronucleus divides into two haploid nuclei; c — two haploid nuclei fuse to form a diploid nucleus

Uniparental isodisomy is the inheritance of two chromatids from a single parent. It occurs as a result of chromatid non-disjunction during the second meiotic division. The zygote receives two copies of a chromosome from one parent and one chromosome from the other, rendering it trisomic. Subsequently, due to the trisomy rescue mechanism described above, the embryonic Cells retain two identical copies of a chromosome from one parent.

A second possible mechanism for uniparental isodisomy formation is monosomy rescue. The zygote receives a chromosome from only one parent and becomes monosomic, after which rescue occurs via selective chromosome duplication. As a result, the cell acquires two copies of the same homolog.

The frequency of uniparental disomy is estimated to be 1 in 3,000 zygotes. It has been described for all pairs of autosomes as well as sex chromosomes (both X and Y). Despite having a normal chromosome set in cases of uniparental disomy and isodisomy, individuals may develop hereditary disorders. This is explained by genomic imprinting (differences in the functional activity of certain maternal and paternal genes during embryonic development). Such conditions are known as Genomic Imprinting Disorders, Examples of which are listed in Table 2.8.

Uniparental isodisomy can lead to the unusual inheritance of two recessive alleles from a single parent who is a heterozygous carrier of a recessive pathological Gene. For instance, uniparental disomy in humans was first described by I. M. Morrison and A. E. Reeve (1988) in a girl with cystic fibrosis (an autosomal recessive disorder). The mother was a heterozygous carrier of the cystic fibrosis gene (Aa), while the father had a normal genotype (AA). The cystic fibrosis gene is located on chromosome 7. Using DNA probe analysis, isodisomy was detected in the affected girl, indicating the inheritance of two copies of chromosome 7 from the mother. Thus, the girl inherited two recessive genes from her mother. Paternity was confirmed by genomic fingerprinting. The diagram below illustrates a potential mechanism for the formation of uniparental isodisomy in this family.

Scheme 2.4. Example of uniparental isodisomy formation