Translated from Russian to English - www.onlinedoctranslator.

com
 - the science of heredity and
variability

Medical (MG) - the science of the role

heredity
geneticsin human pathology, patterns of transmission of
hereditary diseases, their diagnosis, treatment, prevention.

Clinical genetics is an applied MG aimed at applying

the achievements of genetics and MG to solve the
clinical problems of patients and their families.
Stages of development of medical genetics

1. Domaineval period
Mopertii v 1750 described that polydactyly can be
transmitted in an autosomal dominant manner by either
parent. At the beginning of the 19th century, some
patterns of inheritance of hemophilia were identified.
- 1859 - Charles Darwin "The Origin of Species";
- Gregor Mendel in 1865 Publishes the results of studying
the rules of inheritance of various traits in peas.

- 1879 - Flemming's first observation of mitosis;

Stages of development of medical genetics
2. Mendelian period
a. Mendel's first law - the law
uniformity of first generation
hybrids. The trait that manifested
itself in the hybrids of the first
generation was called by Mendel as
dominant, and not the manifested
trait - recessive.
Domination is not always absolute.
b. Mendel's second law - law
splitting signs. In the second
generation of hybrids, plants
appeared, both with a dominant and
a recessive trait, in
average, in a ratio of 3: 1.
v. Independent law
combining features.
1965 - "Experiments on plant hybrids" in
the Proceedings of the Society of
Brunnian Naturalists
 The main tasks of medical
genetics include:
- analysis of the causes of hereditary diseases(NB), the
nature of their inheritance in different families,

- the prevalence of NP in human populations,

- study of specific molecular mechanisms,starting

the pathological process.

- search for possible approaches to prevention and

treatmenthereditary diseases.
1.Hereditary diseases are part of the general hereditary
variability of a person
2. Pathogenesis and clinic of any NB depends on the genotype and environment

3.In the process of evolution, the gene pool of mankind has

accumulated many different mutations
4.The constantly changing environment has led to the emergence
of new types of hereditary pathology - ecogenetic diseases
5.The progress of medicine contributes to the accumulation of
harmful mutations in society, but at the same time increases the
possibilities of diagnosis, treatment and prevention of NB.
6.Decoding of the human genome marks the transition of all
medicine to a qualitatively new level, the distinctive features
of which are a preventive focus and an individual (personified)
approach to the patient.
 NB part of hereditary variability (NI)
• Mutations causes of all NB

•
able-bodied individuals subject to
natural selection
- Mutation cargo 1 mutation per 10 gametes
-
- Substitutional load effect upon changing environmental
) control for
conditions
•
HH level, frequency of sentinel phenotypes
Early detection
counseling of newwith
of families mutations Genetic
ND Creating
conditions so that mutations do not appear
- Gene - a section of a chromosome or DNA that carries information
about the structure of one protein or functional RNA.
- Genotype is a collection of genes.
- Phenotype - a set of signs of an organism.
-
- Variants of hereditary factors or alternativesgene states
(dominant, recessive) are calledalleles...

-The genotype can be homozygous in the presence of two identical

alleles (AA or aa) or heterozygous if the alleles are different (Aa).
Sometimes the relationship of dominance and recessiveness is
absent and both alleles appear in the phenotype. This type of
relationship of alleles is calledcodominance...

- Genome - the complete composition of a cell's DNA, that is, the totality of all
genes and intergenic regions. It can be considered that the genome is a
complete set of instructions for the formation and functioning of an individual.
Objectives of the clinical examination:
• Make an accurate diagnosis
• Establish the nature of the disease
• Send for additional laboratory tests

During the inspection, pay attention

to:
• Congenital malformations
• Anthropometric data
• Congenital anatomical variations
Methods of human genetics
Modern human genetics operates with great
a set of research methods. Let's take a closer
look at the main of these methods:
- Genealogical method
- Twin method
- Population method
- Cytogenetic method
- Biochemical methods
- Molecular genetic methods
 Genealogical method
- was proposed in 1883 F. Galton.
- Based on the construction of pedigrees and tracking ina
number of generations of transmission of a certain
characteristic. This method belongs to the most versatile
methods of human genetics. It is widely used to solve
theoretical and applied problems.

- The method allows you to set:

- 1) whether this trait is hereditary (according to its
manifestation in relatives);
- 2) the type and nature of inheritance (dominant
or recessive, autosomal or gonosomal);
- 3) zygosity of persons of pedigree (homo- or heterozygote);
- 4) gene penetrance (frequency of its manifestation);
- 5) the likelihood of having a child with
hereditary pathology (genetic risk).
Establishing the hereditary nature of the trait Clarifying
the type of transmission of NB
Analysis of the penetrance and expressiveness of the
trait
Linkage of a trait with genetic and
molecular markers
Medical genetic counseling
Proband - a patient
or his relative,
from which the compilation of
the pedigree begins.
The pedigree is collected one or more
featured.
Depending on the purpose of the study, pedigree
can be complete or limited.
The proband must know well the relatives along the line
mother and father of at least three generations and their
state of health, which is extremely rare.
The stages of genealogical analysis consist of
1) collecting data on all blood relatives of the subject (proband)
with the widest possible coverage of information along the
ascending and descending lines, as well as in lateral
directions;
2) graphic construction of the pedigree, accompanied
by explanatory descriptions (legend);
3) analysis of the pedigree and the formulation of conclusions.
The rules for building a pedigree:
- 1) they begin to build a pedigree from a proband;
- 2) each generation is numbered with Roman numerals on the left;
3) symbols denoting individuals of one generation are located on a
horizontal line and numbered in Arabic numerals. The basis of the
pedigree is the proband - the person with whom the study of the family
begins. In pedigrees, the proband is marked with an arrow.
- The first task in the analysis
pedigree - establishing
the hereditary nature of
the trait. If in
pedigree, the same
symptom (disease) occurs
several times, then you can
think about it
hereditary nature.
- After discovering
the hereditary nature of the
trait (disease)
necessary set inheritance
type... For this, the
principles are used
genetic analysis and various
statistical methods for the
processing of data from
many pedigrees.
Symbols used when drawing up
pedigrees
Autosomal dominant (achondroplasia, Marfan
neurofibromatosis, myotonic dystrophy, Huntington's
syndrome,
chorea)
- population frequency - 0.5-1.0%

• Traceable in pedigrees only vertically

• The ratio of sick and healthy children is 1: 1
• Healthy children from sick parents have healthy
offspring
• The ratio of sick boys and girls is the same
• Patients, regardless of gender, are equally likely to transmit the
disease
• In homozygotes, the disease is often lethal.
Autosomal recessive (cystic fibrosis, PKU,
mucopolysaccharidoses) - population frequency -
AGS,
0.25%
• Parents are clinically healthy
• The ratio of sick and healthy children is 1: 3
• If both spouses are sick, children are always sick.
• Both sexes are affected equally often.
• Consanguinity of spouses is not excluded
• In the marriage of the patient and the carrier, 50% of the
sick, the sick and the healthy are born - only healthy are born
 X-linked diseases
- population frequency
Recessive 0.25%
inheritance (Duchenne myodystrophy,
hemophilia, Martin-Bell, Lesh-Nihan, Hunter
syndromes)
- Only boys get sick
- 2/3 of cases are inherited from carrier mothers, 1/3
are spontaneous (sporadic) cases
- Sisters of sick brothers in 50% - carriers of the mutation
- Healthy men do not transmit disease
X-linked dominant inheritance (disease
Retta, vitamin D resistant rickets)
• Boys are affected 2 times more often than girls
• Women get sick less severely, transmit the disease 50% to
sons and 50% to daughters
• Sick men transmit the disease to all daughters
Y permatogenesis, growth
body, limbs, teeth)

M th
eskaya
atia,
progressive ophthalmoplegia)
• The disease is transmitted only through the maternal line
• Boys and girls get sick
• Sick men do not transmit the disease to their offspring
 Epigenetic diseases (imprinting)

Imprinting - differential expression

genes or the manifestation of a mutation
depending on their parental origin

The number of imprinted genes - 200-500

Currently, 10 hereditary
imprinting syndromes (Prader-Willie or
Angelman; Wiedemann-Beckwith;
Silver;
Russell-homogeneous disomy
syndromes)
Imprinting plays an important role in
oncogenesis.
 Twin method
introduced into medical practice by F. Galton in
1875.
- based on the
phenomenonmultiple
pregnancy in humans and
allows you to determine
relative role
genotype and environment in
the manifestation of traits.
- Distinguish between monozygous
and dizygotic twins.
- Spawn rate
twins in humans
is about 1% (1/3
monozygous, 2/3
dizygotic).
- Monozygous (identical) twins develop fromone
fertilized egg. Monozygous twins have exactly the
same nuclear genotype, but may differ in phenotype,
which is due to the influence of environmental
factors.

- Monozygotic twins have a high degree of similarityby

traits
that are mainly determined by the genotype. For example,
they are always the same sex, they have the same blood
groups for different systems (ABO, Rh, MN, etc.), the same
eye color, the same type
dermatoglyphic patterns on fingers and palms, etc.
These phenotypic features are used as criteria for
diagnosing zygosity in twins.

- Dizygotic (fraternal, twins) twins developafter

fertilization by sperm of several simultaneously
matured eggs (polio). Such twins have a different
genotype, and their phenotypic differences are due to
both genotype and environmental factors.
The percentage of similarity of twins for the studied trait is called
concordance, and the percentage of difference is discordance... When
comparing monozygotic and dizygotic twins, the coefficient of paired
concordance is determined, indicating the proportion of twin pairs in
which the studied trait manifested itself in both partners. This
coefficient is expressed as a percentage or in fractions of a unit and is
determined by the formula: K = C / C + D, where C is the number of
concordant pairs, D is the number of discordant pairs.

Since monozygous twins have the same genotype, then

Their concordance is higher than that of dizygotic ones.

Signs Concordance,%
MB DB
Blood group (AB0) 100.0 46.0
Hair color 97.0 23.0
Eye color 99.5 28.0
92.0 40.0
Papillary patterns
67.0 12.1
Schizophrenia 37.0
84.0
Diabetes 18.2
45.5
Clubfoot 66.7 23.0
Tuberculosis 97.4 95.7
Measles
19.0 4.8
Bronchial
asthma
- To quantify the roleof heredity and the environment
in the development of a particular trait, the
heritability coefficient is usually used, calculated
according to the Holzinger formula:

N = KMB (%) - KDB (%) / 100% -KDB (%)

- where H is the coefficient of heritability, KMB -

concordance of monozygotic twins, KDB -
concordance of dizygotic twins. If the result of
calculations according to the Holzinger formula
approaches unity, then the main role in the
development of the trait belongs to
heredity, and vice versa, the closer the result to
zero,
the greater the role of environmental factors.
 Population method
Population genetics methods are widely used
in human research to solve
the following tasks:
- studying the frequency of genes, alleles and
genotypes inpopulations (including genes that
cause hereditary diseases);

-analysis of the laws of the mutational process in

populations;

- comparison of the role of genotype and

environmentalfactors in the formation of human
phenotypic polymorphism in many ways, as well as
in the occurrence of diseases with a hereditary
predisposition.
 Population method
- The method is based on the Hardy - Weinberg law.
This law turns out to be quite suitable for the
analysis of genetic processes in large populations
(populations of more than 4.5 thousand people are
considered large) where relatively free
interbreeding takes place.
- Statistical analysis of distributionindividual
hereditary traits (genes) in human populations
in different countries allows you to determine
the adaptive value of specific genotypes.
 Cytogenetic method
Used to study the normal karyotype
human,
as well as in the diagnosis of hereditary
diseases associated with genomic
and chromosomal mutations.

In addition, this method is used in the study

mutagenic action of various chemicals,
pesticides, insecticides,
medicines, etc.
 Stages of the cytogenetic method
- cultivation of human cells
(usually lymphocytes) on
artificial nutrient media;

- stimulation of mitosis
phytohemagglutinin
(PHA);
- the addition of the alkaloid
colchicine (destroys the spindle
filaments) to stop mitosis at
the metaphase stage;
- treatment of cells with a hypotonic
solution, as a result of which
chromosomes "crumble" and lie
free;
- simple and differential
staining of chromosomes;
- study of chromosomes under
microscope and
photography;
- cutting out individual chromosomes
 Methods for differential
staining of human chromosomes
-V 70th the years XX century were developed methods

differential staining of human chromosomes, which showed that

each pair of chromosomes has its own specific pattern of
alternation of unstained, light and dark-colored discs (Paris
classification of human chromosomes). The development of
special staining methods greatly simplified the recognition of all
human chromosomes, and in conjunction with the genealogical
method and methods of cell and genetic engineering made it
possible to correlate genes with specific regions of
chromosomes. The complex application of these methods
underlies the mapping of human chromosomes.
 Differential staining methods
human chromosomes

Schematic
image
differentially
painted
human
chromosomes
according to

international
classification
 Molecular cytogenetic methods
- Based on fluorescent hybridization technology in situ(FISH).
- For the studied chromosome or its section, a single-strandedthe
piece of DNA to which is attached biotin and digoxigenin...
- This "tagged" piece of DNA is called a probe. OnIn a microscopic
preparation, chromosomal DNA is denatured in situ by alkaline
treatment, that is, the bonds between two DNA strands are
severed.
- The drug is treated with a probe. Since the sequencethe nucleotides of the probe
and the corresponding section of the studied chromosome are complementary,
then the probe is attached to the chromosome.
- DNA renaturation takes place in this region.

- Next, the drug is processed streptovidin (substance, selectively

attaching to biotin) and anti-digoxigenin antibody(selectively binds to
digoxigeninattachments m
raiders rhodamine Red
color or fluorescein green Colour).
- A special fluorescent microscope clearly showsstained
chromosomes against the background of unstained ones.
- Using the method FISH can determine the localization of genes in
chromosomes and all chromosomal aberrations.
Molecular cytogenetic methods
- 24-color FISH of human chromosomes:
- a - metaphase plate;
- b - chromosome layout.

(from Rubtsov N.B., Karamysheva T.V. Vestn. VOGiS, 2000).

 WCP-7

ISH
chromosome-specific NK

a"
47, Y, + mar

ori
DXZ D18Z1

45, X 47, XX, + i (18p) 46, XY, t (4; 15)

 Biochemical methods
- Hereditary diseases, which are caused by gene mutations that change the structure or rate of
protein synthesis, are usually accompanied by a violation of carbohydrate, protein, lipid and
other types of metabolism. Hereditary metabolic defects can be diagnosed by determining
the structure of an altered protein or its amount, identifying defective enzymes, or detecting
metabolic intermediates in extracellular body fluids (blood, urine, sweat, etc.)

- In addition to identifying homozygous carriers of mutant genes, there are methods for

identifying heterozygous carriers of some recessive genes, which is especially important in

medical genetic counseling.

- So, in phenotypically normal heterozygotes for phenylketonuria, after taking phenylalanine,

its increased content in the blood is found.

- In hemophilia, the heterozygous carriage of the mutant gene can be established by

determining the activity of the enzyme changed as a result of the mutation.
 Molecular genetic methods
- They allow you to analyze DNA fragments, find and isolate individual genes
and their segments, and establish the nucleotide sequence in them.

- The DNA cloning method allows you to isolate individual genes ortheir
parts, create an unlimited number of their copies, transcribe and
translate isolated genes, which became possible thanks to the
discovery of enzymes - restriction enzymes. These enzymes
"recognize" a specific oligonucleotide sequence in double-stranded
DNA and cut it at this site. Different restriction enzymes recognize
different nucleotide sequences and cut DNA at different sites.
• The object of research is a DNA molecule
• DNA diagnostics is possible at any stage of
ontogenesis
• Two options for DNA diagnostics:
- direct - detection of mutations
-indirect - identification of a DNA marker linked to a
mutation or to a mutant gene
PRINCIPLES OF DNA DIAGNOSTICS
• Base pair complementarity
• Separation of DNA strands when heated -
denaturation
• Combining complementary circuits during
cooling -
renaturation
• The presence of specific endonucleases
• Separation of DNA fragments by electrophoresis in
gels
 Methods for detecting mutations
I. Search for unknown mutations
- conformational polymorphism of single-stranded
fragments -SSCP
- gralient denaturing gel electrophoresis DGGE
- chemical cleavage of non-complementary
sitesCMC
- heteroduplex analysis -HA
- direct sequencing -DS
II. Identification of known mutations
- Blot - Southern hybridization (1975)
- Polymerase chain reaction -PCR (1985)
- Diagnostics using biochips ( 2,000)
 Microbiochip technology
Engelhardt Institute of Molecular Biology RAS, Moscow
 H I AM
GENOME IN THE "POSTGENOMIC" ERA?
• Identification of genes and gene networks of
frequent multifactorial diseases;
•Diagnosis of diseases by expression profiles of thousands of
genes;
• Diagnostics of hereditary predisposition by testing allelic
variants of "sense" SNPs;
• Introduction of predictive genetic testing of families with a high
risk of frequent multifactorial diseases;
• Creation of individual, family and specialized DNA databases
(genetic passport of a pregnant woman, athlete, conscript,
etc.);
•Creation of new targeted drugs for individual molecular
therapy.
 Molecular genetic methods
- For receiving sufficient
quantity fragments DNA
used by polymerase
chain reaction (PCR) - a method of
selective amplification of individual
regions of DNA by simulating in
vitro DNA replication.
- To carry out PCR, you needthe
presence of primers (forward -
"Forward" and reverse - "Revers"),
- Taq polymerase,
- mixtures of deoxynucleotide
triphosphates (dATP, dTTP, dGTP, dCTP),
- buffer and
- detectable DNA sample.
 PCR method
The PCR method can be used to synthesize a DNA fragment in
vitro and obtain it as a chemically pure substance.
For synthesis, short synthetic
pieces of DNA called primers (primers for
synthesis).
Synthesis of a DNA fragment begins from the 3'-end of the primer
along the template strand, to which it is annealed (adheres
during the complementary interaction between the
nucleotides of the primer and the template).
In one cycle of completing DNA from two strands of DNA
get 4.
In the next cycle, 4 threads will already be 8, etc.
Each cycle takes several minutes.
For 30 PCR cycles, the desired fragment will multiply in 1
a billion times, which allows you to observe the
fragment (after coloring).
 Molecular genetic methods
- To identify specific DNA fragmentsmethod used
Southern blot hybridization... This technique
consists of the following steps:

- 1. After the end of electrophoresis, the gels are placed in

an alkaline solution to denature DNA fragments - single-
stranded DNA is obtained.
- 2. Single-stranded DNA is washed out of the gel onto
nitrocellulose or nylon filters perpendicular to the
surface of the gel with a buffer current.
-3. Single-stranded DNA fragments are fixed on a
filter.
 Blo hybridization according to Southern
4. For visual identification of
the desired fragments, the
test sample is hybridized
with a specific nucleotide
radioactively labeled
sequences or
fluorescent label
oligonucleotide
synthetic probe.
5. Radioactively
reveal
labeled sites by
exhibiting filter with
x-ray film
(autoradiography).
6. Fluorescent marks are
detected in a fluorescent
microscope.

This method allows you to detect

the only gene among dozens
thousand.

(from obi.img.ras.ru/humbio/har)
- The human genome is the genome
biological species Homo sapiens.
-
- Normally, human cells should46
chromosomes are present: 44 of
them do not depend on sex
(autosomal chromosomes), and two -
the X chromosome and the Y
chromosome - determine the sex (XY
- in men or XX - in women), these 46
chromosomes make up one genome.

- The haploid genome contains 3.1

billion base pairs of DNA, which
contain 25,000 genes.
-
- Only for 1.5% of all DNA codes for
protein, the rest is non-coding DNA.
Clinical manifestations of NB
• family character
• chronic, recurrent course
• drug resistance
• specific "marker" symptoms
• systemic damage to organs and tissues
 Semiotics of hereditary diseases
The terms "syndrome" and "disease" for hereditary
pathologies are equivalent. For some nosological
forms,
both terms are used (Down syndrome / disease = trisomy
21).

Semiotics is the methodological basis of an objective medical

examination aimed at identifying a specific hereditary
pathology in a proband on the basis of determining the
characteristic signs of the pathological process and the
dynamics of clinical manifestations. For this purpose,
various subject-shaped signs are used to designate the
signs of NB.
Typical "signs" (symptoms) of NB
"face of an elf "with Williams syndrome (BP NB, 1:10 000)
 Cat scream syndrome
(5p-) 1:45 000

microcephaly

ptosis, hypertelorism

low location and

deformation of the
auricles

skin folds in front of the ear

epicant

antimongoloid eye incision

micrognathia
 Schmid-Frakkaro syndrome or
cat's eye syndrome
1: 1,000,000 population (22pter-22q11 - partial three (tetra) somia 22

Vertical coloboma
irises

low-lying and
deformed
ear shells

microphthalmos

epicant

antimongoloi
d eye incision

mental
retardation
development

heart defects and skeletal

•Lethality - 70% of all human zygotes

• Newborns with NB and congenital malformations 5-5.5%

• Developmental defects - 2.5% of newborns

• Hereditary diseases - 1.5%

Chromosomal - Genetic - 1.0%

0.5%
• Diseases with a pronounced hereditary

predisposition (children under 5 years of age) - 3-3.5%

• All known NB - more than 4,000

• The share of the most frequent NBs under 5 years - > 50%

• Number of infertile married couples - 10-

15%
• Every year in Russia is born 100,000 disabled children
 I Genetic
Gene NB (monogenic)
Multifactorial NB (polygenic or hereditary diseases)

Chromosomal NB
Genetic diseases of somatic cells
Mitochondrial diseases
Epigenetic diseases (imprinting diseases)
Expansion diseases (dynamic
mutations)
I By inheritance type: III By clinical manifestation:
Autosomal dominant Organo-systemic
Autosomal recessive classification:
Locked to the floor nervous,
X-linked dominant X- muscular, ocular,
linked recessive Y- diseases of the musculoskeletal
linked system, etc.
Unconventional type of inheritance
IV By pathogenesis:
Metabolic disorders (1)
Abnormalities of morphogenesis
(2) Combined (1)
and (2)
 Clinical polymorphism (KP)
primary CP - variety of manifestationssigns of NB
associated with a primary defect,
secondary gearbox - complications due
primary defect
penetrance - the frequency of the symptom
among patients
expressiveness - severity of clinicalsign

genetic polymorphism - molecular

basisKP

different mutations of the same gene - different clinic,

different diseases
 AGE OF MANIFESTATION

CHRONIC CHARACTER OF THE CURRENT

MULTIPLE LOSSES

RESISTANCE TO TRADITIONAL
THERAPIES
 Family character of NB
- The presence of similar cases of the disease in the family

- The disease of only one member in the pedigree

is notexcludes NB (may be sporadic)

- If a family case is found, the NB is compiledpedigree

to determine the nature of inheritance (AD, AR, X-
linked)
 NB Manifestation
- More 25% of all gene NBs and all chromosomal and genomic
NBs are already formed in utero (ichthyosis,
achondroplasia, X-linked hydrocephalus,)

- However, there are NBs that give the first symptoms.only in

adulthood or even in old age. In these cases, they talk about
the so-called. manifestations of the NB.

- For example, cerebellar ataxia is first detected incarriers

of the corresponding mutant gene at the age of 20-30
years.
- Common diseases such as gout, illnessParkinson's and
Alzheimer's disease appear mainly in adulthood or old
age.
 Chronic progressive
recurrent course
- Caused by the constant action of a mutant gene

- The chronization and progression of the same NB have

different severity in different patients, which is associated
with the individual interaction of genes

- The recurrent course is due to the peculiarities

functioning of genes and exposure to environmental
factors (malnutrition, hypothermia, infections, stress)

- Examples: progressive disorders:

- motor activity with Duchenne muscular dystrophy,
- digestion with celiac disease, cystic fibrosis,
- respiratory organs (pneumonia with bronchiectasis) with cystic fibrosis
 Specific symptoms of NB
Lens subluxation or dislocation (Marfan syndrome, Weil-Marchesani
syndrome, homocystinuria)

Blue sclera (osteogenesis imperfecta)

Darkening of the urine (alkaptonuria)

Mouse odor (phenylketonuria)

Bleeding (von Willebrand disease, hemophilia)

Rough facial features (mucopolysacchardia)

Asthenic physique and chest deformity (Marfan syndrome)

Short stature, disproportionate limbs and facial skull (achondroplasia)

It is caused by the pleiotropic action of the gene (the effect of one gene on
the development of several traits).

Any monogenic NB is always manifested by a complex of disorders of

various organs and systems.

Secondary pleiotropy is associated with complications of primary

pathological processes:
Cystic fibrosis (mutation of a transmembrane ion transport protein
in cells>

thickened mucus of the bronchi and pancreas> secondary

pulmonary infections and digestive disorders)
Thalassemia (hemoglobin gene mutation>
increased
hematopoiesis> organ
hemosiderosis>
 Primary pleiotropy
Symptoms of NB are due to the effect of the action of the primary products of the
mutant alleles of the gene.
Phenylketonuria

mutation of the phenylalanine-4-hydroxylase

gene, which converts phenylalanine to tyrosine

not synthesized accumulation of phenylpyruvic

tyrosine acids in the body

education declines
impaired development of the nervous system
melanin

hypopigmentation of the skin, dementia, seizures, tremors,

hair, iris hyperexcitability
 Primary pleiotropy
Symptoms of NB are due to the effect of the action of the primary products of the
mutant alleles of the gene.
Marfan syndrome

fibrillin-1 gene mutation> developmental disorder

connective tissue throughout the body

violation of the structure of the walls subluxation of the lens

vascular (aortic abnormalities)

anomalies in the development of musculoskeletal

motor system,
mitral valve prolpasis chest deformity
 Resistance to the most common
therapies
It is characteristic of neurofibromatosis, Duchenne myodystrophy,
Marfan syndrome, Ehlers-Danlos, all chromosomal and genomes of NB.

For a number of NBs, successful treatment methods have been developed:

Wilson-Konovalov's disease (Penicillamine, Unithiol, vitamin B6, diet
number 5).
Celiac disease (gluten-free diet, vitamins,
enzymes, probiotics).
Phenylketonuria (phenylalanine-restricted diet, use of
tetrahydrobiopterin (phenylalanine hydroxylase
cofactor, phenylalanine lyase, gene therapy).
Cystic fibrosis (enzymes, high protein diet, lactose
restriction, mucolytic therapy)
 Medical genetic counseling
- - branch of preventive medicine, the mainthe
purpose of which is to reduce the number of
genetically determined diseases and congenital
malformations.

- The purpose of genetic counseling is to establishthe

degree of genetic risk in the examined family and
explanation to the spouses in an accessible form of the
medical and genetic report.
Tasks of medical genetic counseling:
- retro- and prospective counseling of families and patients
with hereditary or congenital pathology;

- prenatal diagnosis of congenital and hereditary

diseases;

- assistance to doctors of various specialties in making a

diagnosis of the disease, if this requires special
genetic research methods;

- informing the patient and his family in an accessible form about the
degree of risk of having sick children and assisting them in making a
decision;

- maintaining a territorial register of families and patients with

hereditary and congenital pathology and their dispensary
observation;

- propaganda of medico-genetic knowledge among the population.

- In other words, the task of the genetic
consultation is drawing upgenetic prognosis in
the family of an individual with an anomaly of
physical, mental or sexual development and
choice
preventive measures to prevent
the birth of a sick child.
 Making a genetic prognosis
includes three stages.

- Stage 1... Determination of the degree of genetic risk.

- Genetic risk is understood as the probability (from 0 to
100%) the occurrence of a certain anomaly in the
patient (proband) or his relatives.

- The overall risk of manifestation of genetically determined

anomalies for the European populations are 3-5% (genetic
burden), therefore the risk, which does not exceed 5%, is
regarded as low.

- Genetic risk before 10% is called mildly elevated, up to

20% - moderately elevated and over 20% - high.
- Stage 2... Assessment of the severity of the medical and social
consequences of the alleged anomaly.
- The level of genetic risk is far from alwayscorresponds
to the severity of the expected pathology. For
example, polydactyly (autosomal dominant
inheritance, high genetic risk - at least 50%) can be
easily eliminated
appropriate corrective surgery, and the person can
lead a normal life, while phenylketonuria, the risk of
which in children of heterozygous parents is 25%, is a
serious disease that does not respond well to
treatment. In the second case, the degree of suffering
from a medical point of view and social consequences
for the patient and his family is regarded as severe.
- Stage 3 - a geneticist must assess the prospects for
the use and effectiveness of prenatal diagnostic
methods.

- Advances in this area allow planningchildbirth in

families with a high risk of inheriting severe
pathology (Down's disease,
mucopolysaccharidosis, hemophilia, cystic fibrosis,
etc.), since these diseases can be detected by
prenatal diagnostic methods.
Indications for referring a family to a medical
genetic counseling:

-the presence of similar diseases in several members

families;
- primary infertility of the spouses;
- habitual miscarriage;
-mental and physical lag of the child
development;
- the birth of a child with congenital
malformations;
- primary amenorrhea, especially with
underdevelopmentsecondary sexual characteristics;
- consanguinity between spouses.
 Moral and ethical issues
There are a number of moral and ethical difficulties in
medical and genetic counseling:

- intrusion into family secrets (occurs when collecting datato build

pedigrees, when identifying carriers of a pathological gene,
when passport and biological paternity does not match, etc.; the
problem is solved by the correct attitude of the doctor to the
patient);

- responsibility of the geneticist in case of adviceconsulting on the

basis of a probabilistic forecast (it is necessary that the patient
correctly understands the medico-genetic information, the
consultant should not give categorical advice (the final decision is
taken by the consultants themselves).
 Antenatal (prenatal) diagnosis of NB

- - provides for their timely identification.Thus,

prenatal diagnosis is associated with solving a
number of biological and ethical problems before
the birth of a child, since this is not about curing
the disease, but about
preventing the birth of a child with a pathology that does
not respond to treatment.
 Prenatal diagnostic methods
- Currently used indirect and directmethods of
prenatal diagnosis.

- With indirect methods, a pregnant woman is

examined (obstetric and gynecological methods,
blood serum for alpha- fetoprotein, etc.); with
straight lines - the fruit.
-
- Direct non-invasive (no surgicalinterventions)
methods include ultrasonography; to direct invasive
(with violation of tissue integrity) - fetoscopy,
chorion biopsy,
placentobiopsy, amniocentesis, cordocentesis.
 Indirect methods

- The most widespread is the triadmethods:

- study of the level of alpha-fetoprotein (AFP),

- the content of chorionic gonadotropin (CG) and

-free estriol in the blood of women during 2nd trimester of

pregnancy.

- The content of alpha-fetoprotein is also determined in

amniotic fluid, and free estriol - in the urine of pregnant
women. Deviations in the plasma levels of AFP, hCG, free
estriol in a pregnant woman serve as indicators of a high
risk to the fetus.
 Indirect methods
- In particular, the content of alpha-fetoprotein in
biological fluids increased with multiple
malformations, spinal hernia, hydrocephalus,
anencephaly, malformations of the gastrointestinal
tract and other defects.

- In cases of chromosomal diseases in the fetus (for example,Down's

disease) or the presence of type I diabetes mellitus in a pregnant
woman, on the contrary, the concentration of alpha-fetoprotein in
the blood of pregnant women is reduced.
 Indirect methods
- Chorionic gonadotropin, synthesized by trophoblast of the
placenta, is determined already on the 8-9th days after
conception. In the study of the blood of a woman in the 2nd
trimester of pregnancy, an increase in the level of hCG and its
free beta-subunits indicates a delay in the intrauterine
development of the fetus, a high risk of its antenatal death.

- Content free estriol in biologicalfluids of a pregnant

woman reflects fetoplacental activity and decreases
with fetal pathology and dysfunction of the placenta.
 Direct methods

- Fetoscopy - examination of the fetus with fibrooptican

endoscope inserted into the amniotic cavity through the
anterior wall of the uterus. The method allows you to
examine the fetus, umbilical cord, placenta and make a
biopsy.

- Fetoscopy carries a high risktermination of

pregnancy and is technically difficult,
therefore has limited use...
 Ultrasonography (echography)
- is the use of ultrasoundto obtain
an image of the fetus and its
membranes, the state placenta.

- Beginning with 5th week of

pregnancy you can get a picture
shells of the embryo, and from the 7th
week -
and himself.

- On 12-20 weeks of pregnancy

localization is already possible
placenta, diagnosis
twin pregnancy, anencephaly,
bone defects and neural tube
closure, gastrointestinal
atresia.
 Ultrasonography (echography)

- Ultrasound examination allows you to obtain data onthe size of the fetus
(length of the trunk, thigh, shoulder, diameter of the head), about the
function of the myocardium, about the volume of amniotic fluid and the
size of the placenta.

- Ultrasound can detect a number of developmental anomalies in the

fetus -anencephaly, hydrocephalus, polycystic or agenesis of the
kidneys, dysplasia of the extremities, hypoplasia of the lungs, multiple
congenital defects, heart defects, dropsy (edema) of the fetus and
placenta.
 Amniocentesis
- - getting amnioticfluid and fetal
cells, carried out under the
control of ultrasound, for
subsequent analysis.

- Obtaining the test material(cells

and fluid) possibly at 16 weeks of
gestation.

- Amniotic fluidused for biochemical

research (gene mutations are
detected), and cells - for DNA
analysis (gene mutations are
detected), cytogenetic analysis.
(from R. Lewis, 1994)
 Chorion biopsy, placentobiopsy
- - taking the epithelium of the chorionic
villior placenta for research - carried
out between the 8th and 10th weeks of
pregnancy.

- The resulting fabric is used for

cytogenetic and biochemical
research and DNA analysis.

- With this method you can

identify all types of mutations.

- The advantage of the method is that

that it can be used already in the
early stages of fetal development.

(from R. Lewis, 1994)

- Modern technologies, besidesof the above
methods, allow biopsy of the skin, muscles,
liver of the fetus to diagnose many
hereditary diseases. Risk of termination of
pregnancy when using invasive methods

prenatal diagnosis is 1-2%.

- Further development and

dissemination of methods for prenatal
diagnosis of hereditary diseases will
significantly reduce the incidence of
hereditary pathology in newborns.
Signs of prenatal and postnatal dysmorphogenesis,
necessary for the diagnosis of NB.

SKIN DISEASES

Telangiectasia (Randu-Osler syndrome -

ICD10 - I78.0). AD monogenic NB. 1: 5000

Pigmented spots, fibromas

(neurofibromatosis type 1, monogenic

blood pressure NB. 1: 3000)

 SKIN DISEASES

Hyperkeratosis
(Ichthyosis -

MKD10 - Q80)

Increased compliance
(Ehlers-Danlos syndrome -
ICD10 - Q79.6)
 Skull lesions
microcephaly dolichocephaly
hydrocephalus

tringocephaly acroocephaly
 EAR SHELL ANOMALIES
Anotia (absence of auricles)

Microtia (underdevelopment of the auricles)

Macrotia (oversized auricles)

Deformation, low position, bulging,

deviation back,

curls with a smoothed simplified

pattern, preauricular fistulas,

foul papillomas
 Abnormalities in the development of the eyes

anti-Mongoloid
ptosis
eye cut
 Abnormalities in the development of the eyes

telecant - lateral displacement of the

epicant - a fold at the inner inner corners of the eye while maintaining
corner of the eye interpupillary distance

hypertelorism
hypothelorism - - increased
reduced distance
distance between eye
between eye apples
apples (interpupillary
(interpupillary distance
distance increases)
decreases)
 anomalies in the development of the nose

short

coracoid

saddle nose

wide flat
bridge of nose

flat nose
wings
 JAW ANOMALIES
Progenesis - the lower jaw
protrudes due to its
overdevelopment

Prognathia (retrogenia) - the

upper jaw protrudes
forward with its
hypertrophy or hypotrophy
of the lower
jaw

Macrogeny and Microgeny

(lower jaw)

Macrognotia and micrognotia

(upper jaw)
 DENTAL ANOMALIES
yesystem -
increased
gap
between two
neighboring
teeth

three -
abnormally
big
distance
between the
teeth,
not
owned by
and to the
central
ANOMALIES OF THE NECK

short
long
low hairline pterygoid
folds

ANOMALIES OF THE
BREAST
dolichostenomelia (dolicho - elongated, stenos - narrow, melos -
part of the body)
funnel-shaped
keeled
polythelium (accessory nipples)
nipple hypertelorism
scoliosis
pilonidal fossa (in the coccyx
and sacrum)
LIMB ANOMALIES
hallux valgus
varus deformity
elongation
shortening

poly-, oligo-, brachy-, arach-, syn-, campto- (flexor deformity of the

proximal interphalangeal joint) - dactyly
transverse palmar fold
triphalangeal 1 finger
hollow foot, equine
foot, clubfoot, flat feet

ANOMALIES OF THE
UROGENITAL SYSTEM
cryptorchidism (undescended testicle into the
scrotum) shawl-shaped scrotum
hypospadias (downward displacement of the opening of the