1. Monogenic traits and diseases Marie Černá
Lecture No 423-Heredity

2. Single-gene disorders with classical Mendelian inheritance
Dominant
structural
defects
Recessive
enzyme
Autosomal
Autosomal dominant
Autosomal recessive
X-linked
X-linked dominant
X-linked recessive 2

3. Autosomal dominant trait3

4. Autosomal dominant pedigree4

5. Autosomal dominant:
AD: Aa x aa parents - 1 affected
Aa Aa aa aa children
risk 50%
both affected (Aa x Aa) risk: 75%
one homozygote (AA x aa) risk: 100%

6. AD – gene localization on an autosome
- manifestation already in a heterozygote
- manifestation in a dominant homozygote
in some diseases more severe (lethality)
Pedigree (AD):
occurrence is not dependent on sex
possible transmission from father to son
disease occurrence in each generation
a healthy individual has healthy children
Except: incomplete penetrance, new mutations

7. Autosomal recessive trait7

8. Autosomal recessive pedigree8

9. Autosomal recessive:
AR: Aa x Aa parents = carriers
AA Aa aA aa children
risk: 25%
affected x carrier (aa x Aa) risk: 50%

10. AR – gene localization on an autosome
- manifestation only in a recessive homozygote
Pedigree (AR):
occurrence is not dependent on sex
healthy parents, heterozygotes have sick kids
disease occurrence in siblings
more frequent occurrence in consanguinities

11. X-linked recessive trait11

12. X-linked recessive trait12

13. X-linked recessive pedigree13

14. X-linked recessive:
XR:
father affected mother carrier
XY x XX parents XY x XX
XY XY XX XX children XY XY XX XX
healthy 1/2 affected
carriers 1/2 carriers

15. XR – gene localization on X chromosome
- manifestation in a hemizygote
If woman is affected:
male affected x female carrier - consanguinity
karyotype 45,X
or structural abnormalities in X chromosome
syndrome of testicular feminization
- female with karyotype 46,XY

16. Pedigree (XR): male is a hemizygote (has only one X chromosome)
affected males are in consecutive generations always
through a female lineage
affected fathers have all daughters
- obligatory heterozygotes
impossible transmission from father to son
(sons inherit Y chromosome only)
heterozygote mothers have:
1/2 of sons - affected
1/2 of daughters - carriers
mother of affected son -
a heterozygote or new mutation (in one gamete)
some manifestation in a heterozygote female
- nonrandom X inactivation

17. X-linked dominant:
XD:
father affected mother affected
XY x XX parents XY x XX
XY XY XX XX children XY XY XX XX
healthy 1/2 affected
affected 1/2 affected

18. XD – gene localization on X chromosome
- manifestation in a heterozygote
Pedigree (XD):
affected males (with healthy mates)
have healthy sons and affected daughters
affected females (with healthy mates)
have affected 1/2 of sons and daughters
affected females are more frequent in population than affected males

19. Examples of genetic disorders
Autosomal dominant diseases
The frequent diseases (frequency > 1/2000):
Adult polycystic kidney disease
Nervous defects (mental handicap):
Neurofibromatosis 1 - von Recklinghausen (NF1)
Tuberous sclerosis
Huntington disease (HD)
Red blood cell defects (hemolytic anemia):
Hereditary spherocytosis
Skeletal defects:
Osteogenesis imperfecta
Ehlers-Danlos syndrome
Marfan syndrome (spider man)
Achondroplasia (dwarfism)
Risk of malignancy (mutations of tumor suppressor genes):
Familial adenomatous polyposis coli (FAPC)
Retinoblastoma

20. Polycystic kidney disease

21. von Recklinghausen disease

22. von Recklinghausen disease

23. von Recklinghausen disease

24. Marfan syndrome

25. Marfan syndrome

26. Achondroplasia

27. Achondroplasia

28. Examples of genetic disorders
Autosomal recessive diseases
Primary hemochromatosis (iron accumulation)
Recessive mental retardation, deafness, blindness
Cystic fibrosis (CF) (defective chloride ion transport)
Alpha1-antitrypsin deficiency
Steroid metabolism defects (hormones in adrenal glands):
Congenital adrenal hyperplasia (CAH)
Amino acid metabolism disorders (mental handicap):
Phenylketonuria (PKU)
Lipid metabolism disorders: Smith-Lemli-Opitz sy
Sphingolipidoses: Tay-Sachs disease
Mucopolysaccharidoses
Carbohydrate metabolism + Glycogen storage disorders
Red blood cell defects (hemolytic anemia):
sickle cell disease (qualitative defect)
thalassemia, alpha and beta (quantitative defect)

29. alpha1-antitrypsin deficiency
Genotype MM SS ZZ
Mutation exon exon 5
GAAGTA GAGAAG
Amino-acid p p. 342
glu  val glu  lys
Frequency
Activity (%)

30. alpha1-antitrypsin deficiency

31. Examples of genetic disorders
X-linked recessive diseases
Red and green colour blindness (daltonism)
- mutations of opsin genes (hybrid genes)
X-linked mental retardation:
non-specific
Fragile X syndrome
X-linked muscular dystrophies (dystrophin gene):
Duchenne muscular dystrophy (DMD)
Becker muscular dystrophy (BMD)
X-linked coagulation disorders:
hemophilia A - the deficiency of factor VIII
hemophilia B - the deficiency of factor IX
X-linked dominant diseases
Vitamin D-resistant rickets (hypophosphatemic rickets)

32. Duchenne and Becker muscular dystrophy

33. Duchenne and Becker muscular dystrophy

34. Duchenne and Becker muscular dystrophy

35. Duchenne and Becker muscular dystrophy

36. Duchenne and Becker muscular dystrophy

37. Hemophilia A

38. Hemophilia A

39. Hemophilia A

40. Literature Genetics in Medicine, sixth edition, revised reprint
Thompson & Thompson
Saunders, 2004
Chapter 5: Patterns of Single-Gene Inheritance
pages 51 – 78
Chapter 12: …Basis of Genetic Disease
pages 203 – 254
Clinical Case Studies:1,6,7,8,10,12,16,18,22,23,25,29

41. Literature Medical Genetics at a Glance, second edition,
Dorian J. Pritchard & Bruce R. Korf
Blackwell Publishing, 2008
Part 2: Medical genetics 16-20, 22-23, 44-45
pages 40 – 51, 55 – 61, 107 – 113