Medical Genetics - V. M. Zaporozhan 2005

Chromosomal Disorders
Principles of Medical-Genetic Counseling

The formation of chromosomal and genomic Mutations is spontaneous in the vast majority of cases. Most children with Chromosomal disorders are born to healthy parents As a result of a de novo mutation. Consequently, every family faces a baseline population risk of having a child with a chromosomal abnormality. However, a genetic predisposition to chromosomal disorders does exist. This is evidenced by the higher frequency of chromosomal pathologies in mothers who have previously had children (or fetuses) with chromosomal anomalies or birth defects, as well as in women with a history of recurrent early Pregnancy loss. The risk of fetal chromosomal pathology is highest in parents who carry balanced chromosomal rearrangements or chromosomal mosaicism.

In most cases, genetic risk calculation takes into account the parents' karyotypes, maternal age, and a history of children with chromosomal disorders. Several clinical scenarios can be considered.

CALCULATION OF GENETIC RISK ASSOCIATED WITH CHANGES IN AUTOSOME NUMBER AND Structure

1. Parents with a normal karyotype. In this scenario, the risk for the proband's siblings is estimated using empirical data. Empirical risk is derived from actual statistics obtained through the analysis of families with children affected by chromosomal disorders, utilizing genealogical, twin-study, and population-based Research Methods.

For example, the risk of giving birth to a second child with Down syndrome for a woman under 35 is approximately 1%, whereas for older women, it corresponds to twice the population risk for that specific age group. The recurrence risk for Patau and Edwards syndromes is less than 1%.

The frequency of nondisjunction remains practically stable up to age 30, after which it increases significantly, especially past the age of 35. Overall, it is estimated that 1% of all children born to mothers aged 38–40 have trisomy 21, and 3.7% have another type of chromosomal anomaly (Table 5.9).

Table 5.8. Alterations in serum markers (triple screen test) in certain fetal chromosomal syndromes

Table 5.9. Cumulative risk of having children with trisomies (Down, Patau, Edwards syndromes) relative to maternal age

2. Prognosis in cases of parental mosaicism. When mosaicism is detected in one of the proband's parents, the recurrence risk for siblings is calculated using the following formula:

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where X represents the proportion of the abnormal Cell clone, and K is the elimination coefficient for unbalanced zygotes during Embryogenesis (e.g., K = 0.5 for Down syndrome).

3. Prognosis in familial forms of structural Chromosomal aberrations depends on the specific type of chromosomal rearrangement. Special empirical risk tables are utilized for these calculations.

Unlike simple trisomy, the frequency of translocation forms of chromosomal syndromes does not depend on maternal age and is relatively more common among younger parents. For instance, translocation is identified in 8% of all children with Down syndrome born to women under 30, with one of the parents also being a carrier in 23% of those cases. In children born to older mothers, the translocation variant of Down disease accounts for only 0.4% of cases (due to the proportionally higher incidence of simple trisomies). In familial forms of structural chromosomal anomalies, the theoretical ratios of various generated Gametes and zygotes can be calculated mathematically. However, these calculations are of limited practical value for risk assessment, as the actual proportion of affected offspring is significantly lower than theoretically expected. This discrepancy is attributed to the Selection against unbalanced zygotes during embryogenesis. Consequently, even for familial structural chromosomal anomalies, risk is evaluated based on empirical data.

As a rule, the risk is higher when the maternal genome carries the rearrangement compared to the paternal genome. For common translocations, the empirical risk is approximately 11% when the mother is the carrier, and roughly 2% when the carrier is the father.

In extremely rare instances of translocations involving centric fusion between two homologous Chromosomes (such as a Robertsonian translocation of chromosome 21 onto its homolog), all gametes will inevitably carry either an excess or a deficiency of chromosomal material. Therefore, both the theoretical and actual risk to the offspring of such a carrier is 100%. The inheritance pattern for Down syndrome in this scenario is detailed in the section "Etiology of Chromosomal Disorders." An example of genetic risk calculation for familial translocation Down syndrome is provided in Table 5.10.

Table 5.10. Risk of having an affected child among carriers of Robertsonian translocations

Balanced structural chromosomal anomalies in parents can be a underlying cause of recurrent spontaneous abortions. In such cases, the risk of pregnancy loss also depends on the sex of the mutation carrier and the specific Nature of the rearrangement.

Calculation of genetic risk for chromosomal disorders associated with numerical abnormalities of sex chromosomes

The risk for siblings is generally less than 1% (not exceeding the population baseline). The theoretical recurrence risk for offspring of women with an XXX karyotype and men with XXY or XYY karyotypes is 50% (as the extra chromosome is segregated into 50% of gametes). Nevertheless, the majority of aneuploid embryos are spontaneously aborted, bringing the actual clinical risk down to approximately 10%.