Medical Genetics - V. M. Zaporozhan 2005

Chromosomal Diseases
The Role of Chromosomal and Genomic Mutations in Ontogenesis

At least 10% of spermatozoa and 25% of mature oocytes carry chromosomal or genomic Mutations. From 35% to 50% of human embryos perish at the blastocyst stage, which is prior to implantation. In humans, this early embryonic loss typically goes unnoticed, yet a significant percentage of these embryos exhibit chromosomal rearrangements.

Approximately 15% of all recorded pregnancies end in spontaneous abortions, roughly half of which are attributed to chromosomal abnormalities. Analyses of Spontaneous Abortion material frequently reveal polyploidy (20%), monosomy X (20%), complete autosomal trisomies (50%), and other chromosomal or genomic mutations in 10% of cases (Table 5.1). Trisomies for certain autosomes (1, 5, 6, 11, 19) are extremely rare in eliminated embryos and fetuses, highlighting the critical importance of these Chromosomes for embryonic development. These anomalies either disrupt gametogenesis or halt development during the preimplantation period.

The earlier a Pregnancy is terminated, the higher the probability that it was caused by chromosomal or genomic mutations. For instance, when an abortion occurs within the first 2–4 weeks, chromosomal abnormalities are detected in 60–70% of the aborted embryos. In the first trimester of pregnancy, chromosomal anomalies occur in 50% of abortuses, In the second trimester — in 30%, at 20–27 weeks — in 7% of stillbirths, and finally, 6% of all stillbirths are caused by chromosomal pathology.

If the developmental defects are compatible with life, a child with a chromosomal disorder is born. Chromosomal diseases are diagnosed in 0.5–1% of live births, and their frequency surges up to 40% among newborns presenting with multiple Congenital Malformations.

Chromosomal and genomic mutations play a critical role not only in the pathology of early ontogenesis (gamete mortality, failure to conceive, spontaneous abortion, stillbirth, and chromosomal disease). Chromosomal anomalies also arise in somatic Cells during the postnatal period (somatic mutations) and can trigger malignant tumors. For example, a translocation between chromosomes 9 and 22, which yields the Philadelphia chromosome, is a frequent cause of chronic myeloid leukemia.

Overall, chromosomal and genomic mutations can underlie the following clinical scenarios.

1. Infertility. Between 2% and 4% of infertile couples carry chromosomal and genomic mutations that impair Spermatogenesis or oogenesis, or lead to preimplantation embryonic death. Infertility may result from:

— carrier status of balanced chromosomal mutations;

— microdeletion of the long arm of the Y chromosome in men within the region harboring spermatogenesis-encoding genes, known as the azoospermia factor (AZF) locus;

— Klinefelter syndrome in males (47,XXY karyotype);

— Turner syndrome in females (45,X), among other causes.

2. Spontaneous abortions and stillbirths.

3. Birth of a child with a chromosomal disorder, the symptoms of which may include multiple congenital malformations, psychomotor developmental delay in infants, intellectual disability in older children, growth retardation, and infertility.

4. Malignant tumors, particularly leukemia.