Basics of Medical Genetics - Buzhiyevska T.I. 2001

Genetic monitoring

Genetic monitoring entails tracking the volume and dynamics (rate and spectrum) of the genetic load. The magnitude of the genetic load can be determined through screening programs, which are categorized as mass and selective. Mass screening involves the systematic examination of the entire population or specific groups, such as newborns, adolescents, pregnant women, and military recruits. Implementing this type of screening must be economically viable, meaning that its execution costs should be significantly lower than the state expenditures required for the medical and social care of affected children and adults.

Mass screening allows for the detection of hereditary pathologies before clinical manifestation, enabling preventive Treatment that ensures a child's health within the family and an individual's well-being in society. Mass screenings are large-scale socio-economic programs aimed at identifying relatively common genetic defects (at least 1:50,000) that severely impair an individual's lifespan and capacity for work. Furthermore, mass screening Methods must be relatively simple, inexpensive, rapid (using express assays), and devoid of false-negative results. The primary requirement for a genetic condition proposed for mass screening is its curability. After all, why identify patients when we do not know how, or lack the means, to treat them? Such practices are both unethical and economically unjustified. Under the current economic conditions in Ukraine, two nosological entities meet all these criteria: phenylketonuria and hypothyroidism. Neonatal mass screening for phenylketonuria and hypothyroidism helps preserve the health and intellectual potential of nearly all affected children annually: approximately 5 out of 10,000 newborns, translating to at least 10 children in Kyiv or more than 200 children across Ukraine. These two screening programs must be implemented nationwide with 100% coverage of newborns.

This category also includes mass screening (Ultrasonography) of pregnant women to detect congenital fetal malformations.

All mass screenings must necessarily incorporate a mandatory Second Stage involving more complex, and therefore precise and costly, Diagnostics to rule out false-positive results and monitor treatment efficacy.

Selective screening programs involve examining specific groups of patients after the clinical manifestation of a genetic defect to identify a particular hereditary pathology. Examples include screening all children with intellectual disability for phenylketonuria, or all patients with chronic pulmonary or intestinal conditions and men with Infertility caused by congenital bilateral absence of the vas deferens for cystic fibrosis. The efficacy of such programs is considerably lower because the genetic defect is identified only after clinical onset, which diminishes treatment success. Nonetheless, the information obtained is invaluable for providing MEDICAL Genetic Counseling to the proband and their family members.

The culmination of screening programs and the targeted efforts of the medical-genetic network in providing specialized care to families with hereditary conditions should be the establishment of a population-based registry of genetic defects. Only then can the true magnitude and Structure OF THE current genetic load be accurately determined.

Genetic monitoring of genetic load dynamics and mutation rates must be conducted continuously using a comprehensive set of methods, namely:

1. Phenotypic monitoring: tracking (preferably from birth) the frequency of dominant pathologies characterized by complete penetrance, sufficient expressivity, and the absence of genetic and phenocopies that manifest clinically in early childhood. Such conditions include Achondroplasia, aniridia, and other "sentinel" phenotypes—pathologies where inherited Mutations can be easily distinguished clinically from newly acquired ones. However, more detailed insights into this issue should be provided by hereditary disease registries maintained by medical geneticists.

2. Biochemical Monitoring of novel mutation frequencies: a method based on studying Blood protein polymorphism. This type of monitoring requires analyzing the largest possible number of loci in the maximum number of individuals; consequently, it is extremely costly and has limited efficiency. A proposed modification of this method (by Yu.G. Altukhov) involves biochemical selective monitoring targeting the frequency of novel mutations in monomorphic Proteins (characterized by a very restricted set of existing alleles) among organisms with lethal pathologies (miscarriages, Congenital Malformations, perinatal mortality). This modification does not substantially increase the efficacy of biochemical monitoring, as its primary limitation—shared with other methods—remains the inability to confirm biological paternity to definitively exclude inherited mutations.

3. Cytogenetic monitoring of the frequency of new chromosomal and genomic mutations: a highly costly and labor-intensive approach. It necessitates examining family members to rule out inherited Chromosomal aberrations, variants, or predisposing conditions arising during Meiosis.

4. Molecular-genetic monitoring: currently under development, this approach aims to detect novel mutations at the chromosomal and Mitochondrial DNA levels within germ or somatic Cells, with obligatory paternity confirmation. This represents the monitoring of the future.

5. Monitoring via archival records (N.P. Bochkov): allows researchers to estimate the mutation rate by tracking Changes in the frequencies of lethal and sublethal mutations (miscarriages, prematurity, newborns with congenital malformations, perinatal mortality). Monitoring based on congenital malformations alone cannot determine whether the identified pathology is of mutational or teratogenic origin, let alone quantify the exact number of new mutations.

The effectiveness and success of genetic monitoring depend heavily on the proficiency in genetics possessed by physicians across all specialties, particularly pediatricians, obstetrician-gynecologists, neurologists, nephrologists, psychiatrists, endocrinologists, dermatologists, and pathologists. To improve medical-genetic care and preserve the population's Gene pool, existing medical-genetic facilities must be integrated into a unified, standardized system equipped with modern computerized technology, advanced instrumentation, Reagents, standardized methodologies, and uniform reporting and record-keeping documentation. This will enable the creation of a centralized database dedicated to monitoring the Population Genetics of our country. Furthermore, it must always be borne in mind that while the mutation process forms the foundation of population genetic Variability, its direct impact is relatively modest. The primary drivers shaping changes in population gene pools are natural stabilizing Selection, migration, and random fluctuations (Genetic Drift).

However, these fundamental evolutionary mechanisms are comprehensively examined within The Scope of population genetics.