Mohamed Abu-Bakr MohamedM.B.B.CH

M.SC.DEGREE IN PAEDIATRICSAssistant lecturer of pediatric , AUCH

Clinical geneticist & metabolic diseases specialist

Mode of inheritence

Definitions

Genome:-the total number of genes contained in one cell.

Genotype:-complete genetic structure of an individual.

Phenotype:-the physical appearance of an individual that is produced by the interaction of his genes & environment.

• Karyotype:-systematic arrangement of chromosomes into homologous pairs

• Autosomal chromosome in humans, the 22 pairs of chromosomes that are not the sex chromosomes (XX or XY)

• Sex chromosomes :-pair of chromosomes involved in sex determination; in males, the XY chromosomes; in females, the XX chromosomes

Gene:-the unit of heredity that occupies a specific locus on the chromosome which consists of a DNA sequence that directs synthesis of a specific polypeptide chain.Allele:-alternative forms of a gene that occupy a specific locus .An individual inherits 2 alleles for each gene , one from each parent.Homozygoushaving two identical alleles for a given geneHeterozygoushaving two different alleles for a given gene

Dominant = Ddescribes a trait that is expressed both in homozygous & heterozygous form.DD , Dd , ddRecessive = rdescribes a trait that is only expressed in homozygous form and is masked in heterozygous formRR , Rr , rrCarrier• heterozygous individual who does not display symptoms of a

recessive genetic disorder but can transmit the disorder to his or her offspring.

X-linked pattern of inheritance in which an allele is carried on the X chromosome of the 23rd pair .

Trait:-variation of an expressed characteristic .

Genetic TerminologyTerm Definition

GenerationsP First (parental) generation

F1 children (Latin filii) of generation P

F2 children of generation F1

Chromosomes and Geneschromosome macromolecules found in cells,

consisting of DNA, protein and RNA

gene the unit of heredity of a living organism

locus specific location of a gene, DNA sequence, or position on a chromosome

allele one of a number of alternative forms of the same gene or genetic locus

Term Definition

Dominant and recessivedominant allele an allele that is always expressed if present

recessive allele an allele that is only expressed if the dominant allele is not present

Genotypes and Phenotypes genotype the genetic makeup of a cell, an organism, or an

individual

homozygous contains two of the same allele of a gene

heterozygous contains two different alleles of a gene

phenotype an organism's observable characteristics or traits

true breeding pure-bred, is an organism that always passes down a certain phenotypic trait to its offspring

wild type most common phenotype in nature

mutant physical or genetic difference from a mutation in a gene

Patterns Of Inheritance

• A Pedigree is a chart or family tree that traces the inheritance of a trait.

• Females are always circles, males are always squares

• Half-shaded = carrier of gene (but not affected)

• Solid shaded = affected

• Each horizontal line represents a generation.

• Children will always appear on a line directly below their parents.

Symbols commonly used in Pedigree

1- Mendelian inheritance.2- Non- Mendelian inheritance.

Mendelian inheritance.

Autosomal Recessive InheritanceAutosomal Dominant InheritanceX-Linked Recessive InheritanceX-Linked Dominant Inheritance

Autosomal Recessive Inheritance

Autosomal recessive Pattern of recessive inheritance that corresponds to a gene on one of the 22 autosomal chromosomes.Variants:-RR –> normal.Rr carrier.rr --> diseased

Rr RR

Rr Rr

rr RR

rr rr

Examples of diseases

1.Sickle cell disease2.Cystic fibrosis3.Metabolic diseases4.Thalassemia

Autosomal Dominant Inheritance

Autosomal dominant pattern of dominant inheritance that corresponds to a gene on one of the 22 autosomal chromosomes.Variants:-DD diseased (homozygous)Dd diseased (heterozygous)dd normal

Autosomal dominant• only one copy of a disease allele is necessary for

an individual to be susceptible to expressing the phenotype.

• Autosomal dominant inheritance is often called vertical inheritance because of the transmission from parent to offspring.

• Across a population, the proportion of affected males should be equal to the proportion of affected females.

Dd dd

Autosomal dominant• Variable expressivity: variations of phenotype in individuals carrying a same genotype !!

•Penetrance:- the probability of a gene or genetic trait being expressed

•Complete penetrance: all individuals who have the disease-causing mutation have clinical symptoms of disease

• Incomplete penetrance or reduced penetrance:Some individuals fail to express the trait, even though they carry the disease allele

Incomplete penetrance

Examples of diseases1. NEUROFIBROMATOSIS

Examples of diseases2. ACHONDROPLASIA

Examples of diseases3. OSTEOGENESIS IMPERFECTA

AD disorders can present in a child with normal parents as result of :-

1- New mutation.

2-Variable expression of gene e.g atopy may be expressed as hay fever or bronchial asthma.

3- Variable penetrance ( gene may phenotypically skip one generation).

4- Germ line mosaicism. 5- Illegal son

Co-dominance

AB are codominant A and B have antigenesO no antigene

e.g.: ABO blood group

Means that both alleles are expressed in the phenotype of individuals that have heterozygous alleles

X-Linked Recessive Inheritance

X-Linked recessive inheritance• Two copies of a disease allele on the X chromosome are required for an individual with

two X chromosomes (a female) to be affected with an X-linked recessive disease.

• Since males are hemizygous (they have only one X chromosome), one copy of an X-linked recessive disease allele is affected.

• Females are usually carriers because they only have one copy of the disease allele. • Affected males transmit the disease allele to all of their daughters, who are then

carriers, but to none of their sons.

• Women are affected when they have two copies of the disease allele. All of their sons will be affected, and all of their daughters will be unaffected carriers

Examples of diseases

1.Duchenne Muscular Dystrophy

2.Hemophilia A3. G6PD deficiency.4. Hunter syndrome

X-Linked Dominant Inheritance

X-Linked dominant inheritance• Only one copy of a disease allele on the X

chromosome is required for an individual to be susceptible to an X-linked dominant disease.

• Both males and females can be affected, although males may be more severely affected because they only carry one copy of genes found on the X chromosome.

• When a female is affected, each pregnancy will have a one in two (50%) chance for the offspring to inherit the disease allele. When a male is affected, all his daughters will be affected, but none of his sons will be affected.

Examples 1- vitamin D resistant rickets2- incontinentia pigementi

Y linked Inheritance

• Occurs only in males with father to son transmission.

• e.g :- hairy ear pinna

Non – Mendelian Inheritance

NON-TRADITIONAL INHERITANCE

1- Mitochondrial inheritance 2- Germ cell mosaicism3- Uniparental Disomy4-triplet repeat expansion disorders

Mitochondrial Inheritance

An individual’s mitochondrial genome is entirely derived from the mother because sperm contain few mitochondria, which are typically shed upon fertilization. It follows that mitochondrial disorders exhibit maternal inheritance. A woman with a mitochondrial genetic disorder can have affected offspring of either sex, but an affected father cannot pass on the disease to his offspring .Mitochondrial DNA mutations are often deletions or point mutations; overall, 1 : 400 people has a maternally inherited pathogenic mitochondrial DNA mutation.

• The mitochondria are the cell’s suppliers of energy so the organs that are most affected by the presence of abnormal mitochondria are those that have the greatest energy requirements, such as the brain, muscle, heart, and liver .

• Common manifestations include developmental delay, seizures, cardiac dysfunction, decreased muscle strength and tone, and hearing and vision problems.

• Examples of mitochondrial disorders include I. MELAS (myopathy, encephalopathy, lactic acidosis,

and stroke like episodes), II. MERRF (myoclonic epilepsy associated with ragged

red fibers), and

Germ cell mosaicism• A mutation occurs after fertilization in a cll that gives rise to germ cells

(gonads).

• This may explain how a disease that is dominantly inherited ( e.g osteogenesis imperfecta ) occurs in the offspring of parents neither of who have the disease.

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