Furdela Victoria

MD. Assistant Pediatrics Department #2

GENETICS is the science that deals with

heredity and variation in organisms,

including the genetic features and

constitution of a single organism,

species, or group, and with the

mechanisms by which they are

effected

Genetic DiseasesDiseases with

heredity predisposition

Environmental Diseases

- Cystic fibrosis

- Down syndrome

- Sickle cell disease

- Phenilcetonuriae

- Cardiovascular Disease

- DM type 2

- cancer

- Infection

- Traumas

- burns

Genetic variations cause inherited diseases

- Genes- Environment

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Gene – basic unit of genetic information. Genes determine the inherited characters.

Genome – the collection of genetic information.

Chromosomes – storage units of genes.

DNADNA - is a nucleic acid that contains the genetic instructions specifying the biological development of all cellular forms of life

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Locus – location of a gene/marker on the chromosome.

Allele – one variant form of a gene/marker at a particular locus.

Locus1Possible Alleles: A1,A2

Locus2Possible Alleles: B1,B2,B3

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Most human cells contain 46 chromosomes:

2 sex chromosomes (X,Y):XY – in males.XX – in females.

22 pairs of chromosomes named autosomes.

Phenotype - the physical description of the character in an individual organism i.e a green eyes

Genotype - the genetic constitution of the organism

Mutation - a change in the genetic material, usually rare and pathological

Polymorphism - a change in the genetic material, usually common and not pathological

The colure of eyes, the colour of skin is heredity

The colour and structure of our hair is also heredity

Homozygote - an organism with two identical alleles

Heterozygote - an organism with two different alleles

Hemizygote - having only one copy of a geneMales are hemizygous for most genes on the sex

chromosomes

unreplicatedchromosome

telomeres

centromere

replicatedchromosome

sisterchromatids

Each chromatid consists of a very long strand of DNA. The DNA isroughly colinear with the chromosome but is highly structured aroundhistones and other proteins which serve to condense its length andcontrol the activity of genes.

Telomeres

Centromere

Specialized structuresat chromosome endsthat are important for chromosome stability.

A region within chromosomesthat is required for proper segregation during meiosis

and mitosis.

•monogene disorders (diseases or traits where the phenotypes are largely determined by the action, or lack of action, of mutations at individual loci);•multifactorial traits (diseases or variations where the phenotypes are strongly influenced by the action of mutant alleles at several loci acting in concert);•chromosomal abnormalities (diseases where the phenotypes are largely determined by physical changes in chromosomal structure - deletion, inversion, translocation, insertion, rings, etc., in chromosome number - trisomy or monosomy, or in chromosome origin - uniparental disomy);•mitochondrial inheritance (diseases where the phenotypes are affected by mutations of mitochondrial DNA); and•

Congenital malformations (congenital defects of inner organs or parts of body)

1. Deletion – during cell division, especially meiosis, a piece of the chromosome breaks off, may be an end piece or a middle piece (when two breaks in a chromosome occur).

2. Inversion – a segment of the chromosome is turned 180°, same gene but opposite position

3. Translocation – movement of a chromosome segment from one chromosome to a non-homologous chromosome

4. Duplication – a doubling of a chromosome segment because of attaching a broken piec form a homologous chromosome, or by unequal crossing over.

5. Monosomy – only one of a particular type of chromosome (2n -1)

6. Trisomy – having three of a particular type of chromosome (2n + 1)

7. Polyploidy – having more than two sets of chromosomes; triploids (3n = 3 of each type of chromosome), tetraploids (4n = 4 of each type of chromosome).

Addition or deletion of entire chromosomes or parts of chromosomes

Typically more than 1 gene involved

1% of paediatric admissions and 2.5% of childhood deaths

Classic example is trisomy 21 - Down syndrome

Down SyndromeDown Syndrome

KARYOTYPE

Single mutant gene has a large effect on the patient

Transmitted in a Mendelian fashion Autosomal dominant, autosomal

recessive, X-linked, Y-linked Osteogenesis imperfecta - autosomal

dominant Sickle cell anaemia - autosomal recessive Haemophilia - X-linked

The most common yet still the least understood of human genetic diseases

Result from an interaction of multiple genes, each with a minor effect

The susceptibility alleles are common

Type I and type II diabetes, autism, osteoarthritis

What about mapping polygenic What about mapping polygenic disorders?disorders?

Gene1

Gene 2

Gene 3

Gene 4

PHENOTYPE

Environment

DisorderDisorder Frequency (%)Frequency (%)

SchizophreniaSchizophrenia

AsthmaAsthma

Hypertension (essential)Hypertension (essential)

OsteoarthritisOsteoarthritis

Type II diabetes (NIDDM)Type II diabetes (NIDDM)

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44

55

55

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Polygenic Polygenic diseases are commondiseases are common

Unrelated affected individuals share Unrelated affected individuals share ancestral risk allelesancestral risk alleles

Augustinian Monk at Brno Monastery in Austria (now Czech

Republic)

Not a great teacher but well trained in math, statistics, probability,

physics, and interested in plants and heredity.

While assigned to teach, he was also assigned to

tend the gardens and grow vegetables for the

monks to eat.

Mountains with short, cool growing season meant pea (Pisum

sativum) was an ideal crop plant.

1. The Law of Segregation: Genes exist in pairs and alleles segregate from each other during gamete formation, into equal numbers of gametes. Progeny obtain one determinant from each parent.

2. The Law of Independent AssortmentMembers of one pair of genes (alleles)

segregate independently of members of other pairs.

Standard pedigree symbolsStandard pedigree symbolsMale, Male,

affectedaffected

Female, Female, unaffectedunaffected

Male, Male, deceaseddeceased

MatingMating

ConsanguineousConsanguineousmatingmating

PregnancyPregnancy

Male, heterozygous forMale, heterozygous forautosomal recessive traitautosomal recessive trait

Female, heterozygous forFemale, heterozygous forAutosomal or X-linkedAutosomal or X-linked

recessive traitrecessive trait

Dizygotic Dizygotic (non-identical)(non-identical)

twinstwins

Monozygotic Monozygotic (identical)(identical)

twinstwins

Spontaneous abortion Spontaneous abortion or still birthor still birth

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When studying rare disorders, 5 general patterns of inheritance are observed:

Autosomal recessive Autosomal dominant X-linked recessive X-linked dominant Mitochondrial

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the locus is on an autosomal chromosome and only one mutant allele is required for expression of the phenotype

Affected males and females appear in each generation of the pedigree.

Affected mothers and fathers transmit the phenotype to both sons and daughters.

e.g., Marfan disease.

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the locus is on an autosomal chromosome and both alleles must be mutant alleles to express the phenotype

The disease appears in male and female children of unaffected parents.

e.g., cystic fibrosis

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Affected males pass the disorder to all daughters but to none of their sons.

Affected heterozygous females married to unaffected males pass the condition to half their sons and daughters

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Many more males than females show the disorder.

All the daughters of an affected male are “carriers”.

None of the sons of an affected male show the disorder or are carriers.

e.g., hemophilia

If the locus is on the X chromosome and both alleles must be mutant alleles to express the phenotype in females

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This type of inheritance applies to genes in mitochondrial DNA

Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children.

E.g. Leber's hereditary optic neuropathy (LHON)

Affected individual joining Affected individual joining the family, emphasizing the the family, emphasizing the

common nature of the disease common nature of the disease

An affected individual An affected individual with unaffected parentswith unaffected parents

A polygenic phenotypeA polygenic phenotype

No clear inheritance patternNo clear inheritance pattern

Genetic anamnesis (presents of heredity family diseases, infant death, abortions, fetus

death, long barrenness) Dysmorphic signs Low birth weight High morbidity and mortality Mental retardation Ocular and ear defects Skeleton abnormalities Abnormalities of internal organs

Example of dysmorphic signs

Example of dysmorphic signs

Mongoloid eyes Antimongoloid eyes

Child with congenital pathology Congenital pathology in one of parents

Congenital pathology in relatives

Abnormalities of pregnancy

Drawing the pedigree or family tree

Cytogenetic method Prenatal diagnostics Method of dermatoglyphics Population-statistic method Examination of twins

It is important to draw the pedigree or family. This method helps to show the number of involved family members, their sexes and ages of onset etc.

to determine the type of inheritance and further chances of recurrence of the inherited disorder.

Cytogenetic methodCytogenetic method•This method give us possibility This method give us possibility

to examine to examine X and У sex chromatin and chromosomes to establishestablish karyotype.

The essence of the method consists in the analysis of skin patterns (drawings) on the palms and soles. Most informative method for chromosomal syndromes, when the distal axial triradius detected, an excess of arches on the fingers, the absence of distal interphalangeal creases, radial loops on the I, IV and V fingers, transversal crease (in Down's syndrome in the 40 -60% of cases).

It is very important method of prenatal diagnose which give the possibility to estimate sex of fetus, some hereditary diseases and after genetic counseling to decide the question about abortion

This method study the genetic structure of population, its genetic fund, factors and regularity of keeping and changing in next generation

Twins method •This method helps us to study

the role of environment and heredity in formation of normal and pathologic signs

Avoid of marriage with relatives

Have no child Adoption of child Artificial impregnation Ascertainment the risk of heredity pathology in a family

Gene engineering Forbidding of marriage with relatives

Mixing of population Establishing of recessive genes and their treatment

Both parents should be included in genetic counseling

Enough time should be given for counseling

The counselor should be flexible and should not impose decision on the family