1. Autosomal Dominant Diseases
Medical Genetics
HSSP 2010

2. Sampling of AD conditions
Achondroplasia
Familial hypercholesterolemia
Huntington disease
Marfan syndrome
Some non-syndromic deafness
Many hereditary cancer syndromes

3. Factors that Complicate ‘Classical’ Inheritance Patterns
De novo mutation = New mutation
Delayed age of onset = a person with a certain disease may not show disease phenotype until late in life
Anticipation = progressively earlier onset and increased severity of a disease through generations of a family
Incomplete penetrance = not everyone that has a disease allele will show a disease phenotype
Variable expressivity = the trait my vary in expression, from mild to severe

4. Factors that Complicate ‘Classical’ Inheritance Patterns
Pleiotropy = multiple phenotypic effects of a single allele
Locus heterogeneity = production of identical phenotypes by mutations at two or more different loci
Allelic heterogeneity = multiple mutant alleles at a single locus
Sex-influenced = a non-X-linked trait in which the degree or frequency of expression differs between males and females

5. Source of clinical disease in AD conditions
Haploinsufficiency = having one normal allele is not enough to compensate for the mutation in the other allele
Dominant negative mutation = a mutant allele that disrupts function of the normal allele
Gain-of-function mutation = increase in normal functions of a protein resulting in disease phenotype

6. Pedigree symbols

7. What are the pedigree features?

8. Simplest cases of Autosomal Dominant inheritance
phenotype generally in every generation, ‘vertical’ appearance of transmission
roughly half of each generation affected
unaffected individuals do not transmit phenotype
males and females transmit equally and are affected equally

9. Recurrence risk in AD inheritance
One parent affected, one unaffected:
Offspring 50% affected, 50% unaffected
Both parents affected:
Offspring 75% affected (50% heterozygotes plus 25% homozygotes), 25% unaffected
Differences between those homozygous and heterozygous for disease allele?
New mutations can be a significant source of disease, especially with low fitness

10. AD with incomplete penetrance

11. AD with variable expressivity
Waardenburg syndrome: hearing loss; different color eyes;
White Forelock; premature graying of hair

12. Achondroplasia

13. Achondroplasia Autosomal dominant
Mutation in the fibroblast growth factor receptor 3 (FGFR3) gene
Gly380Arg substitution
Incidence of 1/15,000 to 1/40,000
Mutation lethal in homozygotes

14. Achondroplasia FGFR3 is a tyrosine kinase receptor
Activated FGFR3 inhibits chondrocyte proliferation
Gly380Arg is a gain-of-function mutation that results in constitutively active FGFR3
This leads to negative regulation of bone growth, shortened bones

15. Marfan Syndrome

16. Marfan Syndrome Autosomal dominant Dominant negative mutation
Disproportionately tall stature, lens abnormalities
Incidence of ~1/10,000
~30% due to de novo mutations

17. Marfan Syndrome Mutation in fibrillin 1 (FBN1) gene
Mutant fibrillin inhibits the normal microfibril structure (dominant negative)
Connective tissue does not form correctly

18. CHARGE Syndrome

19. CHARGE Syndrome Autosomal Dominant Multiple congenital malformations
Coloboma, heart defects, atresia of the choanae, retardation of growth and development, genital abnormalities, ear anomalies
Mutation in CHD7, a chromodomain helicase DNA-binding (CHD) gene on chromosome 12
Affects 1 in every 3,000 to 12,000 births
Most are de novo mutations

20. CHARGE Syndrome
CHD7 protein is widely expressed both during development and in adulthood
Mutations are thought to affect gene expression in early development
Haploinsufficiency for gene causes disease

21. Familial Hypercholesterolemia

22. Familial Hypercholesterolemia
Hypercholesterolemia, atherosclerosis, xanthomas, arcus corneae
LDL receptor (LDLR) mutation
Lipid metabolism defects
Affects ~1/500
Familial form represents <5% of hypercholesterolemia cases

23. Familial Hypercholesterolemia
LDLR is a transmembrane glycoprotein
Binds low-density lipoprotein (LDL)
Mutations result from insertions, deletions, or recombination between long repeats
Founder effects seen in some populations
Diet acts as an environmental modifier

24. Holoprosencephaly

25. Holoprosencephaly Autosomal Dominant
Ventral forebrain maldevelopment, facial dysmorphism, developmental delay
Birth incidence of 1/10,000 to 1/12,000
Incomplete penetrance (70%) and variable expressivity
Genetic heterogeneity
Sex-influenced trait

26. Holoprosencephaly Sonic Hedgehog (SHH) mutation
Loss-of-function of SHH protein, which acts as a signaling molecule
Translocation that disrupts upstream enhancer element or chromatin structure (position-effect mutation)
Without SHH, patterning of body is disrupted in early development

27. Holoprosencephaly
Recurrence risk depends on presence of cytogenetic abnormality
If sporatic, recurrence risk is 4-5%
If inherited, recurrence risk is 13-21%
Phenotype of the carrier does not affect risk of having affected child
Can not predict severity of affected child based on phenotype of carrier

28. Neurofibromatosis Type 1 (NF1)

29. NF1 Autosomal dominant inheritance pattern Affects ~1/3500 people
High spontaneous mutation rate
Recurrence rate is about 1%
Fully penetrant, although it has highly variable expressivity
NF protein is a negative regulator of the ras proto-oncogene

30. NF1 A neurofibroma is a mass lesion of the peripheral nervous system
The nf1 gene on chromosome 17
nf1 codes for the neurofibromin protein
246 distinct NF1 mutations so far
Most mutations are point mutations and deletions

31. Waardenburg Syndrome Type 1

32. Waardenburg Syndrome Autosomal dominant
Defects in skin and hair pigmentation, iris coloration, deafness
Affects 1/42,000
Mutation in transcription factors important for development of neural crest derivatives
PAX3 transcription factor is mutated in type 1

33. Huntington’s Disease
George Huntington 33

34. Huntington Disease Autosomal dominant
Motor, cognitive, and psychiatric abnormalities
Progressive disease
Prevalence is population-specific
Reduced penetrance
Variable expressivity

35. Huntington Disease
Triplet repeat expansion of polyglutamine-encoding CAG repeat
Mutant alleles have 36 or more repeats
Normal alleles have repeats
The function of huntingtin protein is unknown, but it is ubiquitously expressed

36. HD Neuropathology
Atrophy of the neostriatum
control HD 36

37. THE MOST FREQUENT HD HAPLOTYPE
S127/S95
S183
S126
S180 HD
S182
S43
S98
RELATED HD HAPLOTYPES ??
CONSENSUS
Chromosome 1 2
S127/S95
S183 3
S126
S180 HD
S182
S43
S98 4
CONSENSUS 5 6 7
Chromosome 8 1 9 2 10 3 4 11 12 5 13 6 14 7 15 8 16 9 17 10 18 11 19 12 20 13 21 22 23
500 kb
500 kb 24 25 37

38. The HD Mutation Normal HD Gene Mutant HD Gene
AAGCCTTTC-----(CAG) CAACAGCCG
TTCGGAAAG-----(GTC) CTTGTCGGC
Primer 1
Primer 2
Normal HD Gene
Mutant HD Gene
AAGCCTTTC-----(CAG)> CAACAGCCG
TTCGGAAAG-----(GTC)> CTTGTCGGC 38

39. Determining HD CAG repeat length
Primer 1
CAGCAGCAG…..
GTCGTCGTC…..
Primer 2
Gel electrophoresis
DNA sequencer
Intensity 1 2
100 40 23
Size 20 17 39

40. HD CAG expansion mutation
Chromosome 4
HD gene
EXPANDED CAG REPEAT
EXPANDED POLYGLUTAMINE
Huntingtin protein 40

41. Distribution of normal and disease HD alleles
Normal alleles HD alleles 41

42. HD CAG repeat length and affected status
CAG Disease status
<27 ‘normal’ Unaffected
‘high normal’ Unaffected
‘incomplete penetrance’ May be affected
40+ ‘fully penetrant’ Affected 42

43. Phenotypic variation in HD patients80 60
Age at Neurologic Onset 40 20 10 20 30 40 50 60 70 80 90
100
110
120
Number of CAG Repeat Units 43

44. Mean and Range in age at onset for a given repeat length
Repeat Size N
Mean Onset
Std
Minimum Onset
Maximum Onset
Range in Onset 40
19 (3.0%)
56.47
10.37
Age 38
Age 74
36 years 41
41 (6.6%)
55.61
9.82
Age 35
Age 82
47 years 42
72 (11.5%)
50.04
7.92
Age 28
Age 68
40 years 43
68 (10.9%)
44.35
8.03
Age 25
Age 60
35 years 44
65 (10.4%)
43.28
6.21
Age 32
Age 66
34 years 45
64 (10.3%)
39.27
6.45
Age 20
Age 50
30 years 46
61 (9.8%)
37.61
5.52
Age 57
32 years 47
48 (7.8%)
33.44
5.13
Age 19
Age 45
26 years 48
34 (5.5%)
33.65
5.92
Age 54
29 years 49
28 (4.5%)
30.18
5.23
Age 18
Age 43
25 years 50
18 (2.9%)
33.39
6.88
Age 46 44

45. HD CAG repeat instability
The expanded CAG repeat is unstable in transmissions to the next generation
Expansion bias accounts for ‘anticipation’
Maternal Repeat Unit
Progeny Repeat Unit
Paternal Repeat Unit
Progeny Repeat Unit 45

47. Instability in male transmissions is reflected
in repeat length variation in sperm
Wheeler et al., J Med Genet. 2007, 44,: 47

48. Extensive neuronal cell loss
The HD CAG repeat is unstable in somatic cells, particularly in the brain.
Extensive neuronal cell loss
No obvious neuronal cell loss
Kennedy et al, 2003.
Hum. Mol. Genet. 12, 48

49. HD pathogenesis is a time-dependent process
Modifiers of Disease Process:
Modifiers of Disease
Rate and Nature
Progression
Intermediate Phenotypes
HD CAGn
End-stage
Disease
Trigger
Overt Disease
Phenotype
Secondary Phenotypes 49

50. Review Triplet repeat expansion
Variable age of onset (Huntington’s Disease)
Sex-influenced
Reduced penetrance (Holoprosencephaly)
Variable expressivity (NF1)
Environmental modifiers (Familial hypercholesterolemia)
Pleiotropy (CHARGE Syndrome)
Anticipation (Huntington’s)
Dominant negative mutations (Marfan Syndrome)