genetics lecvghbbnkkkknbbbbbbture-1600-.ppt

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1. Genetics. Genetics.
Single Gene Single Gene
DefectsDefects
DR MARYAM WAQAR
Assistant Professor Histopath

2. Learning objectivesLearning objectives
1. Define Mendelian disorders
2. Enlist transmission patterns of single-gene
disorders
3. Describe disorders of autosomal dominant
inheritance
4. Describe disorders of autosomal recessive
inheritance
5. Describe x-linked disorders

3. Terminology:Terminology:
1.1.Gene.Gene.
2.2.Alleles- Dominant.Alleles- Dominant.
- Recessive.- Recessive.
3. Nucleotides.3. Nucleotides.
4. Codon.4. Codon.
5. Genetic Code.5. Genetic Code.

4. Gene Gene

Biological unit of heredityBiological unit of heredity

Gene hold the information to build and Gene hold the information to build and
maintain their cells and pass genetic traits to maintain their cells and pass genetic traits to
offspringsoffsprings

In cells, a gene is portion of DNAIn cells, a gene is portion of DNA

5. 
Gene (DNA)Gene (DNA)

RNA formationRNA formation

Protein formationProtein formation

Cell structure + Cell enzymesCell structure + Cell enzymes

cell functioncell function

6. Allele Allele

Is one member of a pair or Is one member of a pair or
series of different forms of series of different forms of
genegene

Homozygous: an organism in Homozygous: an organism in
which two copies of genes are which two copies of genes are
identical ie have same allelesidentical ie have same alleles

Heterozygous: an organism Heterozygous: an organism
which has different alleles of which has different alleles of
genegene

7. Chromosomes Chromosomes

Cromatin :Cromatin : DNA, RNA and Proteins that make DNA, RNA and Proteins that make
up chromosomesup chromosomes

Chromatids :Chromatids : one of the two identical pairs of one of the two identical pairs of
chromosomeschromosomes

Centromere:Centromere: the point where two chromatids the point where two chromatids
attachattach

There are 46 chromosomes, 22 pairs of There are 46 chromosomes, 22 pairs of
autosomes and 1 pair of sex chromosomesautosomes and 1 pair of sex chromosomes

8. 
NUCLEOTIDENUCLEOTIDE: group of molecules that when: group of molecules that when
linked together, form the building blocks of DNAlinked together, form the building blocks of DNA
and RNA; composed of phosphate group, theand RNA; composed of phosphate group, the
bases:adenosine,cytosine,guanine and thymine and a bases:adenosine,cytosine,guanine and thymine and a
pentose sugar.In case of RNA,thymine base is pentose sugar.In case of RNA,thymine base is
replaced by uracil.replaced by uracil.

CODONCODON: series of three adjacent bases in one : series of three adjacent bases in one
polynucleotide chain of a DNA or RNA molecule polynucleotide chain of a DNA or RNA molecule
which codes for a specific amino acidwhich codes for a specific amino acid

9. 
GENETIC CODEGENETIC CODE: the sequence of nucleotides : the sequence of nucleotides
in a DNA or RNA molecule that determines the in a DNA or RNA molecule that determines the
amino acid sequence in the synthesis of proteins.amino acid sequence in the synthesis of proteins.

10. 
Congential DiseaseCongential Disease: Diseases which are present at : Diseases which are present at
birth.birth.

Hereditary/Familial DiseaseHereditary/Familial Disease: Diseases which are : Diseases which are
derived from one’s parents and trasmitted in the derived from one’s parents and trasmitted in the
gametes through the generations.gametes through the generations.

Not all congenital diseases are genetic(congenital Not all congenital diseases are genetic(congenital
Syphilis) and not all genetic diseases are congenital Syphilis) and not all genetic diseases are congenital
(Huntington disease).(Huntington disease).

11. •Point Mutation: Point Mutation:
Substitution of a single
nucleotide base by a
different base.
•
Categorized as:

MissenseMissense
MutationsMutations



NonsenseNonsense
MutationsMutations

12. 
Frameshift Mutations:Frameshift Mutations:
Insertion or deletion of Insertion or deletion of
one or two base pairs one or two base pairs
alters the reading frame alters the reading frame
of the DNAstrand.of the DNAstrand.

13. 
Trinucleotide Repeat Mutations:Trinucleotide Repeat Mutations:
Such type of mutation leads to Such type of mutation leads to
amplification of a sequence of 3 amplification of a sequence of 3
nucleotides as in fragile X nucleotides as in fragile X
chromosome syndrome in which there chromosome syndrome in which there
is a 250 or more repeat of CGG is a 250 or more repeat of CGG
(normally upto 29)(normally upto 29)

14. Classification Of Genetic DiseasesClassification Of Genetic Diseases
Single Gene Defects/Mendelian Disorders.
Disorders with Multifactorial or Polygenic
inheritance.
Cytogenetic Disorders.
Disorders showing atypical patterns of
inheritance.

15. Mendelian Mendelian
DisordersDisorders
A genetic disease caused by a single
mutation in the structure of DNA, which
causes a single basic defect with pathologic
consequences

16. Patterns Of Inheritance:Patterns Of Inheritance:
Autosomal Dominant.
Autosomal Recessive.
X-Linked Recessive.
X-Linked Dominant..

17. 
PenetrancePenetrance refers to the percentage of refers to the percentage of
individuals who carry a particular gene and also individuals who carry a particular gene and also
express the traitexpress the trait

Variable expressivity Variable expressivity refers to variation in the refers to variation in the
effect caused by a particular mutation; thus effect caused by a particular mutation; thus
manifestations of neurofibromatosis type I range manifestations of neurofibromatosis type I range
from brown macules to skin tumors to skeletal from brown macules to skin tumors to skeletal
deformitiesdeformities

18. 
PleiotropismPleiotropism refers to multiple possible end refers to multiple possible end
effects of a single mutant gene; thus, in sickle cell effects of a single mutant gene; thus, in sickle cell
disease, the mutant hemoglobin causes hemolysis disease, the mutant hemoglobin causes hemolysis
and anemia, as well as vascular occlusion leading and anemia, as well as vascular occlusion leading
to splenic infarction and bone necrosisto splenic infarction and bone necrosis

Genetic heterogeneity Genetic heterogeneity refers to multiple different refers to multiple different
mutations leading to the same outcome; thus, mutations leading to the same outcome; thus,
different autosomal recessive mutations can cause different autosomal recessive mutations can cause
childhood deafnesschildhood deafness

19. Autosomal Autosomal
Dominant Dominant
DisordersDisorders

20. Characteristics Characteristics
 Manifested in heterozygous states.
Individuals with these diseases usually have
one affected parent. . When both parents of
an affected individual are normal, a de novo
germ cell mutation is suggested
Clinical onset is variable to late
 Clinical features are modified by penetrance
and expressivity

21. Autosomal dominant cause 3 Autosomal dominant cause 3
types of defectstypes of defects

Mutations in a key structural protein Mutations in a key structural protein (e.g., (e.g.,
collagen)collagen)

Mutations of components in complex metabolic Mutations of components in complex metabolic
pathways pathways (e.g., the low-density lipoprotein (e.g., the low-density lipoprotein
receptor) are often autosomal dominantreceptor) are often autosomal dominant

Mutations in enzymes are usually not Mutations in enzymes are usually not
autosomal dominant autosomal dominant

22. Inheritance Pattern:Inheritance Pattern:
•
Typical mating pattern is
a heterozygous affected
individual with a
homozygous unaffected
individual
•Every child has one
chance in two of having
the disease
• Both sexes are affected
equally

23. Autosomal Dominant disordersAutosomal Dominant disorders

24. Structural Protein Defects:
 Marfan’s Syndrome.
 Ehler-Danlos Syndrome.

25. Marfan’s Marfan’s
Syndrome:Syndrome:

Mutation in the fibrillin gene.
 Fibrillin important component
of microfibrils in Elastin.
Tissues affected are Skeleton,
Eyes and the CVS.
 C/F include tall stature, long
fingers, pigeon breast
deformity, hyper-extensible
joints, high arched palate, BL
subluxation of lens, floppy
Mitral valve, Aortic aneurysm
and dissection, defects in skin
(striae)

26. 
Fibrillin is a glycoprotein component of Fibrillin is a glycoprotein component of
microfibrils that provides a framework for the microfibrils that provides a framework for the
deposition of elastindeposition of elastin

It is especially abundant in the connective tissues It is especially abundant in the connective tissues
of the aorta, ligaments, and cilairy zonules that of the aorta, ligaments, and cilairy zonules that
support the eye lens. The disorder, therefore, support the eye lens. The disorder, therefore,
mostly affects the mostly affects the skeletal, ocular, and skeletal, ocular, and
cardiovascular systemscardiovascular systems

27. Ehler-Danlos Syndrome(Cutis Ehler-Danlos Syndrome(Cutis
Hyperelastica):Hyperelastica):
Characterized by defects in collagen synthesis.
Major manifestations involve:
Skin: Hyperextensible, extremely fragile, and
vulnerable to trauma; wound healing is impaired
Joints: Hypermobile and prone to dislocation
Visceral complications: rupture of the colon and large
arteries, ocular fragility with corneal rupture and retinal
detachment, and diaphragmatic hernia

29. Defects in metabolic pathway Defects in metabolic pathway
proteins:proteins:
Familial Hypercholesterolemia:
• One of the most common mendelian disorders.

•Mutation in the LDL receptor gene.
• Hypercholesterolemia due to impaired LDL transport into
cells.
• Increased risk of atherosclerosis and coronary artery disease.
• Increases Cholesterol leads to formation of Xanthomas.Increases Cholesterol leads to formation of Xanthomas.

31. Autosomal Autosomal
Recessive Recessive
DisordersDisorders

32. CharacteristicsCharacteristics
Largest group of Mendelian Disorders
Affected individuals usually have
unaffected (carrier) parents.
Uniform expression of disease
Early age of onset.
These disorders usually involve Enzymatic
Proteins.(not structural proteins)

33. Pattern Of Inheritance:Pattern Of Inheritance:
1.1. Typical mating pattern is
two heterozygous
unaffected (carrier)
individuals.
2.The trait does not
usually affect the parent,
but siblings may show the
disease.
3.Siblings have one
chance in four of being
affected.
4.Both sexes affected
equally.

34. Autosomal recessive disordersAutosomal recessive disorders

35. Lysosomal storage disordersLysosomal storage disorders

36. Glycogen storage diseassGlycogen storage diseass

37. X-Linked X-Linked
Recessive Recessive
Disorders.Disorders.

38. Characteristics Characteristics

All sex-linked disorders are X-linked and most All sex-linked disorders are X-linked and most
are are recessiverecessive

They are fully expressed in males, because They are fully expressed in males, because
mutant genes on the X chromosome do not mutant genes on the X chromosome do not
have a Y chromosome counterpart (affected have a Y chromosome counterpart (affected
males are hemizygous for the X-linked mutant males are hemizygous for the X-linked mutant
gene)gene)

Heterozygote females usually do not express Heterozygote females usually do not express
the disease due to a paired normal X allelethe disease due to a paired normal X allele

39. 
affected women express the disease and transmit affected women express the disease and transmit
it to 50% of their sons and daughters, while it to 50% of their sons and daughters, while
affected men express the disease and transmit it affected men express the disease and transmit it
to 100% of their daughters and none of their to 100% of their daughters and none of their
sonssons

X-linked X-linked dominant conditions are raredominant conditions are rare

40. Pattern Of Inheritance:
• Disease usually passed on
from carrier mother.
• Expressed in male
offspring, females are
carriers.
• In this case, Recurrence
risk is half of sons are
affected, half of the
daughters are carriers.

41. •
Recurrence
risk:
• All the daughters
are heterozygous
carriers and all the
sons are
homozygous normal.

42. X linked disordersX linked disorders

43. DISORDERS WITH MULTIFACTORIAL
(POLYGENIC)INHERITANCE
Involved in many physiologic
characteristics of humans e.g. height,
weight, hair color
Defined as one governed by additive effect
of two or more genes of small effect but
conditioned by environmental, non genetic
influences

44. The disorder becomes manifested only
when a certain number of effector genes,
as well as conditioning environmental
influences are involved
Rate of recurrence is 2 to 7%

45. COMMON DISEASES ASSOCIATED:
Diabetes mellitus
Hypertension
Gout
Cleft lip and palate
Schizophrenia
Bipolar disorder
Congenital heart disease
Skeletal abnormalities
Neural tube defects
Coronary artery disease

46. Case 1Case 1
1. The young individuals having familial
hypercholestrolemia are most likely to have a
mutation in a gene of following cell surface receptor?
Cortisol
Insulin
LDL cholesterol
Leptin
TGF-α

47. Case 2Case 2
Familial disorders such as type IV Ehlers-Danlos
syndrome that result from abnormalities of collagen
synthesis and present during adulthood have what type
of inheritance pattern?
Autosomal dominant
Autosomal recessive
Mitochondrial
X-linked dominant
X-linked recessive

48. Case 3Case 3
A 13-year-old boy with fasting serum glucose of
275 mg/dL is having the following probable
inheritance pattern of this disease?
Autosomal dominant
Multifactorial
X-linked recessive
Mitochondrial DNA
Autosomal recessive

49. Case 4Case 4
A genetic defect involving which of the
following substances is most likely to be present
in Marfan’s syndrome?
Dystrophin
Collagen
Fibrillin-1
NF1 protein
Spectrin

50. Thankyou