1. PATTERNS OF INHERITANCE
dr. R. Sutomo, Sp.A, Ph.D

2. Pattern of inheritance Why concerns?
Genetic counseling
Impact of genetic counseling
Not for reducing the incidence
Option for therapy frequently unavailable

3. Why genetic counseling?
Recurrence risk assessment
Well-informed-based decision
Psychological impacts
Adjustment
Predicting prognosis

4. Studying pattern of inheritance How to investigate?
Family studies
Drawing a pedigree

5. Family studies
A particular trait or disorder  genetic and hereditary?
observation of the way in which it is transmitted from one generation to another, or
on study of its frequency among relatives
Taking a family history can, in itself, provide a diagnosis

6. Family tree
A family tree is a shorthand system of recording the pertinent information about a family
Begins with the person through whom the family came to the attention of the investigator index case, proband or propositus, or proposita (for female)

7. Mendelian character
Its presence and absence depends on the genotype at a single locus
A certain genotype at one locus is necessary and sufficient for the character to be expressed
Does not mean that the character is programmed by only one pair of genes
± mendelian characters

8. Mendelian inheritance
Remind: dominance and recessiveness are properties of characters, not genes
Character:
Dominant  manifest in heterozygote
Recessive  not manifest in heterozygote

9. Symbols in pedigree
Individuals

10. Symbols in pedigree
Individuals

11. Symbols in pedigree
Relationships

12. Symbols in pedigree
Assisted reproductive scenarios

13. Mendelian inheritance
Autosomal dominant
Autosomal recessive
X-linked dominant
X-linked recessive
Y-linked

14. Basic Mendelian inheritance
Autosomal dominant
Autosomal
recessive
X-linked recessive
X-linked dominant
Y-linked

15. Autosomal dominant inheritance

16. Pedigree of autosomal dominant inheritance

17. Features of AD inheritance
An affected person usually has at least one affected parent
No skipping of generation
Affects either sex
Transmitted by either sex
Affected x unaffected mating  child: 50% chance of being affected (assuming that the affected parent is heterozygous)

18. RISK CALCULATION Dd x dd Dd x Dd ?????? d D Dd dd D d DD Dd dd
Affected : unaffected :

19. Autosomal dominant disorders
Achondroplasia
Myotonic dystrophy
Neurofibromatosis
Osteogenesis imperfecta
Tuberous sclerosis
Facioscapulohumeral dystrophy
Acute intermittent porphyria
Acute intermittent porphyria
Familial breast cancer (BRCA 1, BRCA 2
Familial hypercholesterolemia
Familial adenomatous polyposis
Charcot-Marie-Tooth disease
Huntington disease

20. Unusual autosomal dominant inheritance
Non-penetrance
Variable expression
Anticipation
De novo mutation
Genetic imprinting

21. Non-penetrance
Penetrance: the probability that a person with a certain genotype will manifest the character
Non-penetrance  failure of a dominant character to manifest
Theoretically, dominant character 100% penetrance
In fact  continuum characters:
Fully penetrant mendelian   multifactorials
Complicating the genetic counseling

22. Variable expression
Different family members  different features of the disease/syndrome
Waardenberg syndrome
Hearing loss
Different color eyes
White forelock
Premature graying of hair

23. Genetic anticipation
The phenotype is more severe in successive generation
Unclear mechanism
Examples:
Myotonic dystrophy
Huntington disease

24. Genetic imprinting
Normally, genes are equally express either from paternal or maternal copies
Genetic imprinting: expression depends on the origin of the gene/genes paternal or maternal
Paternal imprinting Prader-Willi syndrome
Maternal imprinting  Angelman syndrome

25. Genetic imprinting
The disorder manifests only when the gene is inherited from the mother

26. Genetic imprinting
The disorder manifests only when the gene is inherited from the father

27. Prader Willy Syndrome Angelman Syndrome
Prevalence: 1/
Chromosome 15q11-q13
Genotipe
Paternal/maternal deletion of 5q11-q13 (70%)
Uniparental disomy (UPD) (25-30%)
Maternal UPD (PWS)
Paternal UPD (AS)
Defect of imprinting center in 15q11-q13
paternal 
(-) 
PWS
maternal 
(-)  AS

29. PRADER-WILLI SYNDROME Obesity Short stature Peeled skin
Almond-shaped eyes
Hypotonicity
Small hands and feet
Narrowed nasal bridge
Down-turned mouth
Narrowed bitemporal
Hypogonadism
Mental reterd
Dysartria
Sticky saliva

30. (Happy puppet syndrome)
ANGELMAN SYNDROME
(Happy puppet syndrome)
Flat occiput
Prominent mandible
Microcephaly(~2 yo)
Hypopigmentation
Strabismus
Contracture
Happy face
Hyperactivity
Ataxic gait
Hand flapping
Puppet-like movement
Wide mouth
Spaced teeth
Chewing/
mouthing >>
Severe MR
Epilepsy
Severe speech imp

31. De novo mutation Newly occured mutation Autosomal recessive?
X-linked recessive?

32. Complicated AD pattern Be familiar with common AD disorders
What’s the shortcut...?
Be familiar with common AD disorders

33. Autosomal recessive inheritance

34. Pedigree of AR inheritance

35. Features of AR inheritance
Affected people are usually born to unaffected parents  WHY?
Parent of affected people are usually asymptomatic carrier
Increased incidence of parental consanguinity  WHY?
Affect either sex
After the birth of an affected child, each subsequent child has a 25% chance of being affected

36. Segregation of AR alleles

37. AR inheritance
affected
carrier

38. Effect of consanguinity on AR inheritance

39. Autosomal recessive disorders

40. Complication to AR inheritance Pseudo-dominant
Common recessive conditions can give a pseudo dominant pedigree pattern
Blood group O may be seen in successive generation because of repeated marriages of group O people with heterozygotes

41. Complication to AR inheritance Pseudo-dominant
A individual who is homozygous for an autosomal recessive disorder marries a carrier of the same disorder, their children have a 1 in 2 (50%) chance of being affected

42. Complication to AR inheritance Complementation
Two affected parents may give unaffected child
The disorder is associated with defect in several genes
The children will be normal whenever the parents carry mutation in different genes
AR congenital profound hearing loss
Usher syndrome: hearing loss + retinitis pigmentosa
Associated with defects in 8 different genes

43. Complementation
Locus heterogeneity
Mutational heterogeneity

44. Genocopy
Disorders with the same phenotype due to different genetic loci
Phenocopy
Disorders with the same phenotype being the result of environmental causes

45. For life we learn, not for school