1. Human Genetic Disorders

2. Types of mutations Genetic disorders occur due to mutations.
Mutations are defined as permanent damage of DNA.
Mutations that affect the germ cells are transmitted to the progeny and may give rise to inherited diseases.
Mutations affecting somatic cells do not cause hereditary disease, but are important factors in the development of cancer and some congenital malformations.

3. Mutations are classified into three categories
Genome mutations: these involve loss or gain of a whole chromosome. Thus genome mutations affect the number of chromosomes
Chromosomes mutations: structural changes within a chromosome due to re-arrangement of genetic material
Gene mutations: affecting individual genes within a chromosome

4. MENDELIAN DISORDERS
They are caused by mutations affecting single genes.
More than 4500 disorder were listed.
These disorders are inherited either as autosomal dominant, autosomal recessive or X-linked inheritance.
It has to be remembered that each gene is represented as a pair (alleles) on a specific gene locus on the corresponding chromosomes.

5. MENDIALIAN DISORDERS
AUTOSOMAL DOMINANT
AUTOSOMAL RECESSIVE
X-LINKED DISORDERS

6. AUTOSOMAL DOMINANT DISORDERS
Definition:
These are disorders manifested in the heterozygous state i.e. resulting from mutations affecting one of a paired allele and the other is not necessarily affected.

7. Examples of autosomal dominant diseases:
Nervous disorders such as neurofibromatosis
Renal disorders such as adult type polycystic kidney
Gastrointestinal disorders as familial polyposis
Skeletal disorders such as Marfan syndrome
Haemopeotic disorders such as hereditary spherocytosis
Metabolic disorders such as familial hypercholesterolemia
Bone disorder such as multiple exostosis

8. NEUROFIBROMATOSIS

9. Polycystic Kidney Disease

10. Marfan's Syndrome Dominant Disorder Connective Tissue defects
1/20,000 people
Connective Tissue defects
Dislocation of lens in eye
Rupture of aorta (weak vessel walls)
“Spider fingers”
Elongated body, face
Caved-in chest

11. Marfan's Syndrome Abraham Lincoln?
Lincoln could have had a mild form of Marfan’s

12. AUTOSOMAL RECESSIVE DISORDERS
Definition:
These are disorders manifested in the homozygous state i.e. resulting from mutation affecting both of a paired allele.
Abnormality of one allele without its corresponding allele results in a heterozygous carrier state without clinical manifestations

13. Examples of autosomal recessive diseases:
Nervous disorders such as spinal muscular atrophy
Renal disorder such as infantile type of polycystic kidney
Haematopoeitic disorders such as sickle cell anemia and thalassaemias
Metabolic disorders such as cystic fibrosis, phenylketonuria, galactosaemia, alpha one anti-trypsin deficiency and haemochromatosis.

14. Sickle Cell Anemia Recessive Defective Haemoglobin yn RBCs
Anemia (loss of blood cells)
Damage to brain, heart, lungs
Primarily in African Americans; 1/10 in US is a carrier

15. X-LINKED DISORDERS Definition: Types:
Disorders resulting from a mutant gene existing in the X chromosome
Types:
May be recessive or rarely dominant:

16. X-linked recessive disorders:
The abnormal (mutant) gene is of a recessive nature.
Thus females are carriers and do not suffer from a clinical disease since the other allele is normal, while males suffer from a disease since the abnormal gene has no corresponding allele on the Y chromosome

17. Examples of X-linked recessive disorders:
Skeletal disorders as Duchenne muscular dystrophy
Haempoeitic disorders as hemophilia A&B
Ocular disorders as color blindness
Immune disorders as agammaglobuniemia
Metabolic disorders as diabetes insipidus

18. Duchenne Muscular Dystrophy
X-linked recessive
Most Common in males
1/3500
Muscle Enlargement
Dystrophin
Protein that provides support for the cell; without it the cell enlarges and explodes

19. Haemophilia X-linked recessive Most Common in males
“Bleeder’s Disease”
Missing clotting factor
Bleeding spontaneously and in joints
Queen Victoria: descendents affected with hemophilia

20. X-linked dominant disorders (rare)
The mutant gene is of a dominant nature, i.e. only one abnormal gene of the allele pair is sufficient to cause disease; therefore the disease affects both males and females
Example:
Vitamin D resistant rickets

21. CYTOGENETIC (CHROMOSOMAL) DISORDERS
The normal human karyotype of somatic cells is 46 chromosomes including 44 (22 pairs) of autosomes and two sex chromosomes either XY (male) or XX (female)
The normal human karyotype (44 XY or 44XX) is symbolized as 2n- diploid.
The normal gamete (sperm or ovum) karyotype is symbolized as in 1n-haploid (22X or 22Y)

22. NORMAL KARYOTYPING

23. Chromosomal abnormalities include:
Structural abnormalities
Numerical (number) abnormalities

24. Numerical (number) abnormalities of chromosomes

25. Numerical (number) abnormalities:
Euploidy:
Euploidy refers to the normal number of chromosomes within the cell; for example the euploid number of chromosomes in a human cell is 46.
Aneuploidy:
Aneuploidy is defined as an abnormal number of chromosomes. Syndromes caused by an extra or missing chromosome are among the most widely recognized genetic disorders in humans.

26. Examples of syndromes with chromosome number abnormalities:
Abnormal number of sex chromosomes:
Klinefelter's syndrome:
Male with karyotype 47XXY, characterized by atrophic testis, infertility and gynaecomastia
Turner's syndrome:
Female with karyotype 45X, characterized by atrophic ovaries, infantile external genitalia, underdeveloped breast, amaenorrhea, infertility, normal or subnormal mentality and may be congenital heart diseases

27. Klinefelter Syndrome Longer fingers and arms Scarce beard Sterile
1 in 1,100 births
47 chromosomes XXY only
#23 Trisomy Nondisjunction
Longer fingers and arms
Scarce beard
Sterile
Delicate skin
Low mental ability
Normal lifespan

28. Klinefelter's Syndrome
George Washington?
No Children – Sterile?
Dental Problems
Height – Very tall for generation
Still Inconclusive

29. Turners Syndrome 96-98% do not survive to birth No menstruation
1 in 5,000 births
45 chromosomes X only
96-98% do not survive to birth
No menstruation
No breast development
Narrow hips
Broad shoulders and neck

30. Turner's Syndrome Monosomy of Sex Chromosomes; XO female Infertile
Dwarfism
Some mental retardation
Webbed Neck

31. Abnormal number of autosomes:
Trisomy 21 ( Down syndrome):
Karyotype: 47 XX or XY +21
Most common type of chromosomal disorders
Incidence: 1:700 births
Risk usually increases with maternal age

32. Down Syndrome Short, broad hands Stubby fingers Rough skin
Impotency in males
Mentally retarded
Small round face
Protruding tongue
Short lifespan

33. Down's Syndrome Trisomy 21 Mild to severe mental retardation
Distinct Facial Features
Heart Defects
Fingerprints – Sworl
Most Common Birth Defect – 1/700 births
Mother’s Age over 40 – 1/80
Problems during Oogenesis

34. Downs Syndrome - Trisomy-21
Simian Crease

35. Edwards syndrome: Karyotype: 47 XX or XY +18
Risk also increase with maternal age

36. Edward's Syndrome Trisomy 18 Elfin Appearance Low set ears
Malformation of many organs – specifically heart/lungs
“Blue Babies” due to lack of oxygen
90% die within first 6 months

37. Patau syndrome: Karyotype; 47XX or XY +13
Risk increase with maternal age

38. Patau's Syndrome Trisomy 13 Cleft Lip and Palate
Polydactyl – more than ten fingers/toes
1/6000 births
Most die within first year

39. Patau’s Trisomy Syndrome
1 in 14,000 births
47 chromosomes XY or XX
#13 Trisomy Nondisjunction
Small head
Small or missing eyes
Heart defects
Extra fingers
Abnormal genitalia
Mentally retarded
Most die a few weeks after birth
Cleft palate

40. THANK YOU & GOOD LUCK