Fundamentals of Medical Genetics - Buzhiyevska T.I. 2001

Methods of Genetic Examination
Clinical and Genealogical Method

The Clinical-Genealogical Method is the primary tool in medical genetics. The majority of hereditary pathologies can be diagnosed precisely through this method of analysis. It requires a thorough and attentive examination of the patient, a targeted medical history focusing on reproductive function and the presence of similar disorders among nuclear family members and across several generations through both the maternal and paternal lines, as well as a clinical examination and interviews with all available relatives of the proband (Fig. 7).

The pedigree must be studied both vertically (from generation to generation) and horizontally (within individual generations).

Based on the clinical findings, the proband's phenotype is mapped out according to a specialized scheme that differs from standard medical records compiled by non-genetic physicians. Phenotypic description begins with an Assessment of the patient's behavior, physical development (height, body weight), social responsiveness, mental status, and intellectual development relative to age. Next, the physician should observe and note the distinctive Features of the proband's appearance: Skull shape, Hair growth pattern, Structure, and distribution; the shape and placement of the auricles (including earlobe notches), eyebrows, palpebral fissures, and the distance between them. The shape of the forehead, Nose, oral fissure, Lips, Tongue, and upper and lower jaws must be described; along with the presence, number, and Specific features of dental formation and eruption; the hard palate, and cleft lip and/or palate; as well as the shape and Proportions of the neck, chest, and spine. It is also necessary to thoroughly examine the upper and lower extremities, describing their shape, digit count, dermatoglyphic patterns (ridges) of the palms and soles, and the positioning of the hands and feet.

Class="center">

Fig. 7. Pedigree of probands D. Diagnosis: Growth Hormone deficiency (absolute Pituitary dwarfism). AR inheritance pattern.

□ — males, о — females (numbers inside indicate age in years); ↗ — proband; □ — relatives deceased from unknown causes; • — miscarriages. 1, 2, 3, etc. — individual number within a generation. 0 — proband's generation. I, II, III — numbers of preceding generations

Subsequently, the physician's attention turns to the condition of the Skin: its elasticity (or lack thereof), hair growth, moisture level, pigmentation, presence of atypical folds, and rashes.

All observed symptoms are recorded using specialized terminology provided in the "Genetic Glossary" section. The accuracy of the diagnosis largely depends on how thoroughly developmental microanomalies are identified—features that physicians typically overlook.

The examination of Internal Organs through Traditional Methods of Palpation, Percussion, and Auscultation concludes the clinical evaluation of the proband. Critical anamnestic data include information regarding the course of Pregnancy, gestational age at birth, birth weight and length, as well as the obstetric and gynecological METABOLISM/13.html">History of the mother and family.

The interviewing and Clinical examination of as many relatives of the proband as possible aims to identify carriers of pathological genes, whether recessive, dominant, or X-linked. Recessive alleles manifest clinically only in the homozygous state (consanguinity is of particular importance here), whereas dominant alleles appear in both homozygous and heterozygous sets.

At the same time, the presence and degree of clinical symptom expression depend on the penetrance and expressivity of a given Gene.

Penetrance refers to the frequency or probability of a dominant gene manifesting phenotypically, expressed as the percentage of individuals in whom the gene is expressed relative to all carriers of that gene. Expressivity denotes the degree of phenotypic manifestation of a gene—the measure of the gene's strength, determined by the severity of the trait's development.

In medical genetics, the term "expressivity" is used with regard to the completeness of the syndrome's manifestation rather than a single isolated symptom, because the syndrome, rather than an individual symptom, is the result of a single mutation (in Mendelian disorders). Often, the expressivity of a monogenic syndrome depends on the proband's sex. The outcome of a clinical-genealogical family examination includes the phenotypic record, the pedigree, the Determination of the inheritance pattern, and a preliminary diagnosis. Graphic symbols are used when constructing the pedigree. In the pedigree (family tree), generations are denoted by Roman numerals starting with the proband's generation (0), and each individual within a generation is designated by Arabic numerals. The individual (proband) who sought medical consultation is indicated by an arrow. Thus, every person in the examined family has an identifier that reflects their position in the pedigree (see Fig. 7).

Following the establishment of a preliminary diagnosis at The First stage (based on clinical-genealogical analysis), Differential diagnosis must be performed to rule out clinically similar syndromes, genocopies, and phenocopies of the pathology in order to verify the diagnosis. Consultations with relevant specialists—such as an ophthalmologist, neurologist, psychiatrist, cardiologist, orthopedist, and others, determined on a case-by-case basis—are widely utilized. Such a proband and family members are prescribed laboratory and instrumental investigations: radiography of the skull, extremities, and spine (to determine bone age and detect anomalies), ultrasound imaging, general Blood and urine tests, as well as functional and laboratory evaluations of the cardiovascular, digestive, respiratory, immune, endocrine, urogenital, and central nervous systems. Once again, the scope and combination of these examinations are based on specific diagnostic hypotheses and the presence or absence of changes characteristic of the suspected pathology. These steps constitute the Second Stage of the medical-genetic examination. In some cases, the results of the patient's endocrine status analysis may be decisive; in others, the immune status or histological examination of biopsy material. Autopsy protocols can significantly assist in establishing a diagnosis in families with a prior history of infant mortality.

Most hereditary syndromes occur very rarely in the population (1×10³ — 1×10⁶); therefore, to verify a diagnosis, specific cases should be compared with those described in the literature (atlases, monographs, catalogs, and computer diagnostic programs such as "Possum"). In cases of hereditary pathology, diagnostic accuracy determines not only the patient's Treatment strategy, prognosis for life and disease progression, but also the success of Genetic Counseling for both the patient (establishing an adaptive environment, choosing a career and a spouse, reproductive forecasting) and their family members (timely identification of affected individuals, prenatal diagnosis, prophylactic treatment, preconception Prevention, and the risk assessment of having affected children).

The foregoing allows for the Conclusion that the diagnosis of hereditary pathology, the success of its treatment, and its prevention depend primarily on the physician's competence, education, and genetic reasoning, rather than on the availability of expensive equipment, Reagents, specialized facilities, and the like.