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 Diseases Diseases 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

4  Gene – basic unit of genetic information. Genes determine the inherited characters.  Genome – the collection of genetic information.  Chromosomes – storage units of genes.  DNA  DNA - is a nucleic acid that contains the genetic instructions specifying the biological development of all cellular forms of life

5  Locus – location of a gene/marker on the chromosome.  Allele – one variant form of a gene/marker at a particular locus. Locus1 Possible Alleles: A1,A2 Locus2 Possible Alleles: B1,B2,B3

6 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

 Homozygote - an organism with two identical alleles  Heterozygote - an organism with two different alleles  Hemizygote - having only one copy of a gene  Males are hemizygous for most genes on the sex chromosomes

a a unreplicated chromosome telomeres centromere replicated chromosome sister chromatids Each chromatid consists of a very long strand of DNA. The DNA is roughly colinear with the chromosome but is highly structured around histones and other proteins which serve to condense its length and control the activity of genes.

Telomeres Centromere Specialized structures at chromosome ends that are important for chromosome stability. A region within chromosomes that 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 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 disorders? Gene1 Gene 2 Gene 3 Gene 4 PHENOTYPE Environment

Disorder Frequency (%) SchizophreniaAsthma Hypertension (essential) Osteoarthritis Type II diabetes (NIDDM) Polygenic diseases are common Unrelated affected individuals share ancestral 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 Assortment Members of one pair of genes (alleles) segregate independently of members of other pairs.

Standard pedigree symbols Male,affected Female,unaffected Male,deceased Mating Consanguineousmating Pregnancy Male, heterozygous for autosomal recessive trait Female, heterozygous for Autosomal or X-linked recessive trait recessive trait Dizygotic(non-identical)twins Monozygotic(identical)twins Spontaneous abortion or still birth

33 When studying rare disorders, 5 general patterns of inheritance are observed:  Autosomal recessive  Autosomal dominant  X-linked recessive  X-linked dominant  Mitochondrial

34  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.

37  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

39  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

40  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

41  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 the family, emphasizing the common nature of the disease An affected individual with unaffected parents A polygenic phenotype No 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

Mongoloid eyesAntimongoloid 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 method This method give us possibility to examine establish This method give us possibility to examine X and У sex chromatin and chromosomes to establish 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 % 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