Monogenic Disease
Medical Genetics
OMIM Statistics for May 5,2004
Autosomal 14353
X-linked 857
Y-linked 48
Mitochondrial 60
15318
http://www.ncbi.nlm.nih.gov/Omim/mimstats.html
Basic Conception
Dominant —— A
Homozygote —— AA or aa
Heterozygote —— Aa
Genotype & Phenotype
Recessive —— a
Proband (Index case)
Pedigree
Ⅰ
Ⅱ
1 2
1 2 3
Proband (Index case)
Pedigree
AD diseases are those in which a single
copy of a mutant gene on autosome is
enough for the trait to be expressed or
shown.
Autosomal Dominant (AD)
Pedigree Characteristics
Aa aa
P ×
1,1
F1
gamete
Each affected individual has one affected
parent
50% of sibs are affected,Males and females
are affected with equal probability
50% of offspring are affected
Passed in a vertical fashion
Pedigree Characteristics
Complete dominance
Incomplete dominance (semidominance)
Codominance
Delayed dominance
Irregular dominance
Sex-influenced dominance
Types of AD
Autosomal Recessive (AR)
Carrier (Aa)
AR diseases are characterized only in
individuals homozygous for the mutant
gene on autosome.
P ×
1,1,1,1
F1
Pedigree Characteristics
gamete
×
1,1
Both parents are carriers
The diseases are sporadic
The risk of offspring is higher in
consanguineous marriage
25% of sibs are affected,Males and females
are affected with equal probability
Pedigree Characteristics
2/3 of unaffected sibs are carriers
1,Small family
Two questions
2,Consanguineous marriage
Autosomal Recessive (AR)
PAH
Phenyllactic
acid
Benzophenone
Autosomal Recessive (AR)
Tyrosinase MelaninDopaPhe
Protein
Tyr
Protein
Phenylypruvic
acid
Phenylacetic
acid
Phenylketonuria,PKUⅠ
MIM 261600
1,Infants with PKU have
a mousy odor
PAH
Phenyllactic
acid
Benzophenone
Phe
Protein
Tyr
Phenylypruvic
acid
Phenylacetic
acid
×
2,Infants with PKU have
fairer hair and skin
3,This disease can cause
significant mental
problems
The gene of Tyrosinase —— 11q14 - q21
Albinism typeⅠ
PAH Tyrosinase MelaninDopaPhe Tyr ×
MIM 203100
MYOPIA
NORMAL
Infantile Severe Myopia
×
1,1
the Risk of AR
in Consanguineous Marriage
1 2
1 2 3 4 5
1 2
Ⅰ
Ⅱ
Ⅲ
Ⅳ 1
the Risk of AR
in Consanguineous Marriage
1
Ⅰ
Ⅱ
Ⅲ
Ⅳ
1 2
1 2 3 4 5
1 2 3
the Risk of AR
in Consanguineous Marriage
1 2
Ⅰ
Ⅱ
Ⅲ
Ⅳ
1 2
1 2 3 4 5
1 2 3
X-linked Inheritance
Criss-cross inheritance
X-linked recessive (XR)
X-linked dominant (XD)
Hemizygote
Y-linked Inheritance
Holandric inheritance
Hairy Ears (MIM 425500)
Genetic Heterogeneity
Allelic heterogeneity
Locus heterogeneity
Phenocopy
Bayes Theorem
Prior probability
Conditioned probability
Joint probability
Posterior probability
Bayes T,1763
AD (incomplete dominance,P)
Bayes Theorem
1 2
Ⅰ
Ⅱ
Ⅲ
1 2
1
AD (delayed dominance)
Bayes Theorem
40
20
1 2
Ⅰ
Ⅱ
Ⅲ
1 2
1
Ⅰ
Ⅱ
Ⅲ
1 2
1 2
1 2
Autosomal recessive
Bayes Theorem
X-linked recessive
Bayes Theorem
1 2 3 4
Ⅰ
Ⅱ
Ⅲ
1 2 3
1
Complete Dominance
Back
Syndactyly typeⅠ (MIM 185900 )
1 2
1 2 3 4
1
Ⅰ
Ⅱ
Ⅲ
Semidominance
Achondroplasia (MIM 100800)
Back
1 2Ⅰ
Ⅱ
Ⅲ
1 2 3
1
Codominance
A gene has more alleles and when the
individual is a heterozygote a different
phenotype is produced than that of either
homozygote.
MN blood group (MIM 111300)
ABO blood group (MIM 110300)
G a l G a lN A c G N A c G a l PS
-N-acetylgalactosaminyltransferase
-3-D-galactosyltransferase
ABO blood group
Back
L-fucose
transferase
H
Gal GalNAcG NAcGal
Fuc
G al G alN A cG N A cG al
A A gFuc
N A cG al
G al G alN A cG N A cG al
B A gFuc
G al
Irregular Dominance
Polydactyly postaxialⅠ (MIM 174200)
1 2 3
1 2 3
1 2 3
1 2Ⅰ
Ⅱ
Ⅲ
Ⅳ
Penetrance
Complete penetramce
Incomplete penetramce
Forme fruste
Skipped generation
Polydactyly postaxialⅠ (MIM 174200)
1 2 3
1 2 3
1 2 3
1 2Ⅰ
Ⅱ
Ⅲ
Ⅳ
Irregular Dominance
Expressivity
Irregular Dominance
Penetrance
1 2 3
Ⅰ
Ⅱ
Ⅲ
Ⅳ
1 2 3
1 2 3
1 2
Osteogenesis imperfecta type Ⅰ (MIM 166200)
Blue sclera
Multiple fracture
Deafness
Marfan syndrome(MIM 134797)
Irregular Dominance
Irregular Dominance
Marfan syndrome(MIM 134797)
Irregular Dominance
Marfan syndrome(MIM 134797)
Back
Irregular Dominance
Marfan syndrome(MIM 134797)
Delayed Dominance
Huntington chorea (MIM 143100)
1 2 3 4 5
Ⅰ
Ⅱ
Ⅲ
1 2
1 2 3
40
42
45
21
32
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80
Exon —— (CAG)n
n ＝ 9～ 34,average 20
n ＝ 37～ 100,average 46
IT15 —— 4p16.3
Genetic imprinting
Dynamic mutation
Back
Huntington chorea (MIM 143100)
1 2 3 4 5
Ⅰ
Ⅱ
Ⅲ
1 2
1 2 3
40
42
45
21
32
Delayed Dominance
Truncate Ascertainment
Complete ascertainment
Incomplete ascertainment
A couple of carrier
One child
Two child
Weinberg proband method
Truncate Ascertainment
C ＝ Σa (r — 1)Σa (s — 1)
Back
Close relatives
Consanguineous Marriage
Ⅰ
Ⅱ
1 2
1 2
a
First degree relatives 0.5
Second degree relatives 0.25
Third degree relatives 0.125
Coefficient of relationship
Consanguineous Marriage
The gene frequency of AR is 0.01
the frequency of carrier is 0.02
Consanguineous Marriage
The gene frequency of AR is 0.001
the frequency of carrier is 0.002
Consanguineous marriage
＞ Random marriage
The rarer the AR is,the higher the risk
should be
Back
Conclusion
Consanguineous Marriage
Pedigree Characteristics
1,1
× ××P
1,1,1,1
F1
gamete
1,1,1,1
More affected males than affected females
Each son has 50% chance of being affected,
each daughter has 50% chance of being a
carrier
Because of criss-cross inheritance,brothers,
sons of mother’s sisters,brothers of mother,
sons of sisters of affected individual have
chance of being affected
Passed with female carriers
Pedigree Characteristics
Pseudohypertrophic
Muscular Dystrophy
Gower sign
Becker (BMD) MIM 300376
Duchenne (DMD) MIM 310200
Familial,X-linked recessive (MIM 306700)
Chromosome,Xq28
Gene,coagulation factor VIIIc
Hemophilia A
Hemophilia A
King George Ⅲ
Prince Albert Queen Victoria
ElizabethⅡ
24 2
3
3 3 2
72
2
Hemophilia A
(MIM 306700) Back
Pedigree Characteristics
×
1,1
×P
1,1,1,1
F1
gamete
The ratio of affected females to the males is
approximately 2 to 1
Each affected individual has one affected parent
All daughters of affected males are affected,
all sons of affected males are normal; 50%
offspring of affected female have chance of
being affected
Passed in a vertical fashion
Pedigree Characteristics
Vitamin D Resistant Rickets
Vitamin D Resistant Rickets (MIM 307800)
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