This document discusses various topics in human genetics including: 1. It defines human genetics as the scientific study of human variation and heredity, and medical genetics as the study of the hereditary nature of human disease. 2. Genetic diseases can be caused by inherited mutations, chromosomal abnormalities, or mutations in somatic cells (cancer). Inherited diseases can be due to nuclear or mitochondrial genetic mutations. 3. Examples of inherited genetic disorders and their inheritance patterns are discussed, including autosomal dominant disorders like achondroplasia and autosomal recessive disorders like thalassemia.

1. HUMAN GENETICS
Dr. D.A.R.K. Dayarathna
MD (medicine –col),
MSc (medical genetics –Ncl - UK)

2. Genetics
• Human genetics- scientific study of
human variation and Heredity
• Medical genetics - study of the hereditary
nature of human disease
• Clinical genetics- Care, diagnosis and
counseling of patients with congenital
malformations or genetic diseases

3. Causes of diseases
• Accidents
• Infections
• Genetic diseases
• Complex traits

4. Genetic diseases
• Inherited diseases
• Diseases due to mutations in somatic
cells- cancer

5. Inherited diseases
• Due to genetic mutations- nuclear,
Mitochondrial
• Chromosomal abnormalities
• Complex traits, multifactorial disorders

6. Mutations
• Deletions- ranging from 1 bp to mega
base
• Insertions- including duplications
• Single base substitution-
• Missense mutations- replace one amino
acid with another in the gene product
• Nonsense mutations replace one amino
acid codon with a stop codon
• Splice site mutations create or destroy
signals for exon/intron splicing
• Frame shifts can be produced by

7. Mutation- functional change
• Loss of function mutations
• Gain of function mutations

8. Loss of function
• Autosomal recessive disorders

10. Autosomal dominant
• Dominant negative
• Haplo insufficiency

11. Dominant negative mutation

13. Karyotype

15. Gene structure and protein
synthesis

17. GENE expression

18. Down syndrome

20. Down syndrome
• Common cause for • Screening – triple test
mental retardation - alpha feto
• Most are due to protien
trisomy -oestriol
21,nodisjunction
- chorionic
• Elderly mothers are gonadotopihic
more suseptible hormone
• 2-3% due to - ultra sound
translocatin of 21to14 scan
-amniocentesis

21. Turner syndrome

22. Klinefelter syndrome

23. Fragile X syndrome

24. Fragile X syndrome
• Inherited cause of
intellectual disability
• Large protruding
ears,large testiclesle
• Due to mutation of the
fragile X mentel
retardation 1 ( FMRI)
• X linked dominent
condition with variable
expressivity

25. Autosomal dominant inheritance
• Males and females are equally affected
• Transmission between all sexes are
observed . Male to male, female to male
• Symptoms usually appear later in life
• Pleiotrophy- single gene disorder produce
multiple phenotypic effect
• Variable expressivity of gene
• Reduced or incomplete penetrance, the

26. Autosomal dominant ctd
• Codominance- when both traits are
expressed fully in heterozygous state. Ex-
AB blood group
• Intermediate inheritance
• Ex- sickle cell trait

27. Pedigree symbols

29. Achondroplasia
•Common genetic cause
of dwarfism
•Mutation in the fibroblast
growth factor receptor
3(FGFR3)
•Cause abnormality of
cartilage formation
•Can be detected before
birth by prenatal
ultrasound

30. Autosomal dominant polycystic
kidney disease
•Inherited systemic
disease
• 1 in 400 to 1 in 1000
•Mutation in PKD1 and
PKD 2 gene
•Cyst in liver, pancreas,
cerebral aneurysm, mitral
valve prolapse.
•Imaging and molecular
studies

31. Neurofibramatosis
•Skin fibromas
•Neuro fibromas
•Capu lau spot
•Variable clinical
manifestation

32. Hereditary spherocytosis

33. Hypertropic obstructive
cardiomyopathy
• Presentation
Sudden death
Chest pain on excretion
palpitation

34. Mafan syndrome

35. Osteogenesis imperfecta

36. Familial hypercholesterolemia

37. Brugada Syndrome
• More in asia
• Cause of sudden death
in young
• Can present with
atypical chest pain and
recurrent palpitation
• Mutation in sodium ion
channels
• Cause of death is VF
• Implantable
cardioverter defibrillator

39. Autosomal recessive
inheritance
• Presentation - in early age, usually with
severe symptoms
• Affect either sex
• Affected people are usually born to
unaffected parents
• Parents are usually asymptomatic carriers
• Increase incidence of parental consanguinity
• After the birth of an effected child, each
subsequent child has a 25% of being
Affected

40. Autosomal recessecive pedigree

41. Thalasaemia

43. Albinism

44. White Tiger

45. X linked recessive inheritance
• Affect mainly males
• Affected males are usually born to un
affected parents
• Mother is normally an asymptomatic
carrier
• There is no male to male transmission in
the pedigree

47. Color blindness(X-linked)

49. Duchenne muscular dystrophy
• Common inherited
muscular dystrophy
• Mutation in dystrophin
gene
• Symptoms before age
of 05
• Progressive muscle
weakness
• Pseudo hypertrophy
of calf muscles
• Cardiac involvement

50. Lyon hypothesis
• Random inactivation
of one X chromosome
in early foetal
development

52. X linked dominant inheritance
• Affect either sex but more female then
males
• Female are often more mildly and more
variably then males
• No male to male transmission

54. Mitochondrial inheritance
• Matrineal inheritance
• Variable clinical manifestation due to
heteroplasmy

57. Mitochondrial inheritance ctd

58. Mitochondrial disease
• Ragged Red Fibers" -
clumps of diseased
mitochondria accumulate
in the subsarcolemmal
region of the muscle fiber
and appear as "Ragged
Red Fibers" when muscle
is stained with modified
Gömöri trichrome stain

59. E/M view of diseased mitochondria

60. Mitochondrial myopathies
• Kern sayare
syndrome
• Chronic progressive
external
opthalmoplegia

61. Complex traits
Diabetes mellitus, Hypertension,
mental disorders etc

62. Complex traits ctd
• Gene and environment interaction
• Population studies
• Family studies
• Twin studies