(Mendelian Disorder Single Gene Disorder)

.,Ph.D.

1)
2) autosomal dominant , recessive X-linked
3) autosomal dominant , recessive X-linked
4)
5)
(autosome) 22
X Y
(Mendelian or single gene disorder)

(genotype) (phenotype) (locus) (allele) (autosome)
(sex-chromosome) (homozygote) (heterozygote) (hemizygote)


2 1

( 1 )
ABO ABO 2 A A A B B
B A O B O O O AA , AB , BB , AO , BO , OO
A, AB, B, A, B, O AA, BB OO
AB, AO BO
X X y
X
X

A a

B B

A and B are loci.

A or a is an allele of locus A.
Locus A is heterozygous but

locus B is homozygous

1 loci, homozygous heterozygous

(meiosis) 50 % x
50 % X 100 %
Y
(dominant)
2 (recessive)

autosomal dominant, autosomal recessive sex linked X-linked disorder ( link
X-linked X )
OMIM (Online Mendelian Inheritance in Man)
6000 autosomal dominant 66% autosomal recessive
27% 6 % X-linked
1%
(dominant & recessive gene)
(autosomal dominant disorder)


2

 semidominant

(carrier)

(autosomal domiant disorder)

() 1 1,000 1 10,000
1 (1,000)2 1
(10,000)2 (incidence)

(pedigree) ( 2)
2
1) (generation)
2) ()
3) (risk)
50 % ( 3 )
4)
3
50%
50% 50% 50%

 2
2) isolate case 2) 2) non-penetrance

3 mating diagram heterozygote normal.

mutant allele normal allele
4

 ( 2)
2
(isolate case) isolate case
(new mutation)
2

non-penetrance ( new mulation
isolate case non-penetrance )
(new mutation)
(DNA
replication)

isolate case ()




X-linked

(paternal age)

achondroplasia
1 x 10 5 (1 100,000 ) 45 4 achondroplasia
4 x 10 5 4 100,00 )

DNA
1 10,000 1
30,000 3
5




50% (1
100,000)
(non pentrance)

achondroplasia 80%
familial hypercholesterolemia

(fitness)
fitness

Note : fitness
fitness = 1 1
Gonadal Mosaicism

gonadal mosaicism
gonadalmosaicism

gonadal mosaicism
osteogenesis imperfecta
(Note : osteogenesis imperfecta )
Achondroplasia

Familial hypercholesterolemia cholesterol )

Variation in Expression

( neurofibromatosis type I )
6

 (neurofibromas) neurofibromas
2 caf-au-lait
spot neurofibromas
variation in expression variation in expression
(genetic make up) (stochastic chance)
variation in expression 2
1) Varition in the degree and type of clinical manifestation
2) Variation in the time of onset
Varition in the degree and type of clinical manifestation

Variation in the time of onset Huntington
chorea 20-40
(sex
influenced variation in manifestation) hemochromatosis

neurofibromas
caf-au-lait spot 4 5
The Concept of Penetrance
nonpenetrance
penetrance
100% penetrance incomplete penetrance, reduced penetrance partial
penetrance
non- penetrance

Molecular and Biochemical Basis of Dominant Disease

1. Loss of an Alele Function

(homcostasis) (feed back mechanism)
mechanism familial hypercholesterolemia LDL receptor defect
LDL receptor LSL (low density lipoprotein) LDL
2. Dominant Negative Mutation
osteogenesis inperfecta
collagen fiber collagen collagen fiber
triple helix collagen
3. Gain of Function
amyloidosis
4. Two Hit Hypothesis

(somatic cell)
retinoblastoma, familial breast
cancer ( cancer genetics)

1) Achondroplasia

(dwarfism) (short-limb dwarfism)

(rhizomelic shortening of the limbs) (frontal bossing) (mid-face
hypoplasia) (lumbar lordosis)
(limitation of elbow extension) genu vacuum hydrocephalus,
(intracranial bleeding during delivary) (brain stem compression)
(base of skull) foramen magnum

complete penctrance (3.3 x 10 (-5) 1

) semidominant
( )
8

 4 p fivroblast growth factor recptor-3 (FGF 3) (prevalence)

achondroplasia 0.5-1.5
2) Neurofibromatosis Type (NF 1)

NF1 caf-aulait spots c]t

neurofibromatosis axillary freckles Lisch nodules (hamartoma iris)
variation of expression pleiotropy
(epilepsy) 10% optic
gliomas 13% neurofibromas 2-4% pheochromocyloma
(Note : pleiotrophy )

complete penetrance 50%

)
neurofibromin 17q neurofibromin GTPase

3. Marfan Syndrome

Marfan sysdrome fibrous connective tissue

3
variation of expression pleiotroply
scoliosis lordosis
(myopia) (ectopialentis)
mitral value prolapse, mitral regurgitation, dilatation of aortic root aortic regurgitation
aortic aneurysm aortic dissection

Marfan syndrome 25%

fibrillin-1 15

4. Huntington Disease (HD)

HD
(choreic movement) (dementia)
30 40 10-20

HD Huntington 4p 16.3
3 trinucleotide repeates CAG CAG repeat Huntington
9 37 38-86
triplet repeat expansion ( anticipation)
5. Adult Polycystic Kidney Disease (APKD)
APKD (renal eyst ) (liver cyst)
(intracranial aneurysm)
30
40
(chronic renal failure)
APKD APKD genetic heterogeneity
APKD APKD 90% PBP
16 10%
(Note : genetic heterogeneity )
APKD 3 1 1,000
2 3 1 3 6-12 x 10-5
Variation in age of onset
(ultrasound) 22% 10 68% 11-20 86% 2030
6. Familial Hypercholesteroleemia(FHC, type II hyperlipoproteinemia or LDL receptor defect)
FHC 1 500
(myocardial infarction) 60 5%
FHC
LDL receptor gene LDL (low density liipoprotein)
LDL cholesterol cholesterol
coronary artery disease
10

 semidominant cholesterol
homozygote cholesterol 700 mg/dl

10-20 heterozygote
40-60 cholesterol 250-450 mg/dl

FHC
(
molecular genetics)
osteogenesis imperfecta (OI) Ehler Danlos syndrome
collagen dominant negative mutation
familial breast
cancer ( 5% ) familial polyposis of colon ( 1% )
hereditary non-polyposis of colon cancer (HNPCC, 5% )
retionoblastoma, wilm tumor ()
(autosomal recessive disorder)

2
compound heterozygote


1/4 (25%)
() 1/2 (50%) 1/4 (25%) 4 mating
diagram (1/4) (1/2) (1/4)

horizontal
transmission ( 5 )

11

 4 mating diagram heterozygote carrier (clinically

normal) Mutant allele normal allele

5 autosomal recessive inheritance

12

 5 5
isolate case 5 5
horizontal transmission 5
pseudo-dominant vertical transmission

(gene grequency) -thalassemia
Simple Risk Calculations
genetic counseling

-thalassemia
counselor



6
% shared genes ()


1

13

Relation
Relative x Spouse ( = f) x =
(f l)

1/1 x f x 1/4 = f1

2/3 x f x 1/4 = f1
(-)
1/2 x f x 1/4 = f1
(first cousin) 1/4 x f x 1/4 = f1

f x f x 1/4 = f1

Consanguinity ()
( 1:10,000 1:100,000 )





(perinatal mortality), congenital malformations
- 30-50%
(first cousins) 4-5%
(2-3%)
Autosomal Recessive and Population Genetics

()

Fitness

fitness

haplotype (linkedalleles)
14

 haplotype
linkage disequilibrium


carrier frequency = (disease frequency1/2) x 2
Hardy Weinberg law
p2 + 2pq + q2 = 1
p = frequency common allele , q = frequency rare allele
P2 = frequency normol (homozygous)
2pq = frequency carrier (heterozygote)
q2 = frequency disease (homozygote)
2pq () 2q p
2q = (q2)1/2 x 2 = () 1/2 x 2
adrenogenital syndrome 100
(100/106)1/2 x 2 = 20 1000
Autosomal Recessive Phenotypes in the Local Population

thalassemia sickle
cell anemia () Tay-Sachs cystic fibrosis

1. Founder Effect

2. Selective Advantage
sickle cell

3. Genetic Drift
4. Meiotic Drift meiosis
()

15

5. Racial, Geographic and Ethnic Differences

(genetic
diversity)
Population Based Heterozygote Screening (Carrier Screening)


CF
Molecular and Biochemical Basis of Recessive Disease

2
(loss of function)


Genetic Heterogeneity
compound heterozygote (
)
-Thelassemia minor major -globin
genetic heterogeneity allelic heterogeneity
deafness ()
genetic heterogeneity locus heterogeneity nonallelic heterogeneity
double heterozygote
locus heterogencity ? Charcot Marie Tooth
X-linked

- Hemoglobin disorder
- Enzyme deficiencies ( hemoglobinopathy inherited biochemical
disorder)

16

Sex Linked Principles

X linked Y linked inheritance X Y
X Y
(fertilization) X X
Y X X
XY X Y 7
X
X Y

7 mating diagram X-linked heterozygote carrier

mutant allele normal allele
Y linked inheritance Y linked
(hairy ear rims)
Y linked inheritance X-linked inheritance
()

17

 X - inactivation
X linked dominant hypophosphatemia
X linked recessive X linked inheritance
X linked recessive
X linked dominant recessive X linked inheritance
X linked X ( 7)
() 50%
50% 100%
50%
8 X linked 8
X linked 8
isolate case X linked allele

50%

8 X linked inheritance
18

New Mutation and X linked Disorders

X-linked X-linked dominant

isolate case X linked recessive X linked

isolate case

1/3 2/3 ( )
1/3 2/3 2/3 X
1/3 X
X ()
2/3 X
2/3
Lyon Mechanism of X-inactivation
Lyon hypothesis X-inactivation X
X
32-128 X X DNA
methylation heterochromatin 32-128
X inactivated (random) X
(maternally derived X chromosome)
mosaic X X
32-128
Lyon hypothesis
X ( G6PD) X
X linked coat colour mutation
wild type X-inactivation
Bar body

19

 X X
inactivated heterochromatin
X-inactivation
1. (carrier) X-inactivation Duchenne
muscular dystrophy X

2. (patchy)
incontinentia pigmenti calico cat
3. X
inactivated target cells
4. X
(selective X-inactivation) X X-linked
agammaglobulinemia lymphocyte () X
inactivated agammaglobulinemia

X-linked recessive
X-inactivation

1. Unlucky Lyonization X

2. Turner syndrome (45.X)

3.
4. X autosomal translocation
5. ( autosomal genocopy X-linked )
X-linked
1. Duchenne Becker Muscular Dystrophy (DMD BMD)

DMD: 3-5 severe skeletal muscle degeneration, calf

pseudohypertophy, progressive muscle weakness 8-11

20

 (respiratory failure)
2 0
BMD: BMD DMD
BMD 10-20 respiratory failure
30
Incidence: DMD single gene defect 1 3,500
BMD 1 20,000
Genetics:X linked inheritance DMD BMD
X dystrophin dystrophin 2.3
dystrophin sheletal cardiac muscle cell membrane
membrane dystrophin membrane
skeletal muscle degeneration muscle
weakness
pseudo - hypertrophy
Mutation: dystrophin gene rearrangement
70% DMD gene rearrangement 65% partial deletion 5% partial
gene duplication 30% point mutation, undetectable (small)
deletion or duplication etc.
BMD deletion duplication dystrophin deletion
duplication dystrophin codon deletion duplication (In frame deletion or
duplication) deletion duplication DMD frameshift mutation
deletion
frameshift mutation DMD
deletion In frame BMD
2. Fraglle X syndrome
Down syndrome
incidence 1 1,000 1 2,000 fragile X
syndrome fragile
X syndrome
fragile site x Xq27.3
, Hyperactivity, Autism, Macroorchidism ()
Variation of
Expression
21

Genetics: fragile X syndrome X-linked

20% Pedigree
(non penetrance)
transmitting male
fragile X syndrome microsatellite triplet repeat
sequence CGG FMR-1 CGG repeats FMR-1 6-54
repeats CGG repeats FMR-1 200 repeats transmitting
male repeat 52-193 repeats
FMR 1 CGG repeats
CGG
6-54 repeats (stable) CGG repeat 52-193 repeat CGG repeat
stable 200 repeats female meiosis CGC repeat
52-193 repeats Unstable permutation CGG repeats 200 repeats
FMR (no expression) fragile X full mutatioin
trinucleotide repeats triplet repeat expansion

1. Jorde LB, Carey JC and White RL.eds. Medical Genetics. Mosby, 1995
2. Beaudet AL, Scriver CR,Sly WS and Valle D, Genetics, Biochemistry and Molecular Basis of Variant Human
Phenotypes. In Seriver CR. Beaudet AL. Sly WS and Valle D eds. The Metabolec and Molecular Basis of
inherited Disease 7 ed McGraw-Hill, lnc, 1995,53-118
3. Vogel Fand Motulsky AG. eds Vogle Motulsky Human Genetics Problem and Approaches 2 ed 1986
4. Caskey CT. Presymptomatic Diagnosis:A First Step Toward Genetic Health Car Science 1993;262;48-49
5. Thompson MW, Mclnnes RR, and Willard HF eds, Thompson & Thompson Genetics m Medicine 5 ed 1991
6. Gelehrter TD and Collins FS. Eds Principles of Medical Genetics 1990
7. Mendel GJ. 1865 Versche iiber Pflanzenhybriden. Verhandlungen des Naturforschenden Vereins (Biunn)
8. McKusick VA. Ed The JohnsHopkers University Online Mendelian lnheritance in Man
9. Bellus GA, et al, Achondroplasia is defined by recurrence G830R mutation of FGFR3 Am.J.Hum.Genet
56:368-3731995
10. Online Mendelian lnheritance in Man# 100800 Achondroplasia
11. Online Mendelian lnheritance in Man#162200 Neurofibromatosis (Vaon Recklinghausen Disease;
Neurofibromatosis, Type l; NF1; Neurofibromin, included)
12. McKusick VA ed. Online Mendelian lnherifance in Man#154700 MARFAN Syndrome(MFS, MGSl)
22

13. McKusick VA ed. The John Hopkins University Online Mendelian lnheritance in Man#143100 Huntington
Disease (HD;Huntington Chorea; Huntingtin, included)
14. McKusick VA ed. The John Hopkins University online Mendelian lnheritance in Man#173900 Polycysic
Kidneys (Adult Polycystic Kidney Disease; APKD; PICD;PKDl; Potter Type lll Polycystic kidney Disease;
Polycystin, included).
15. McKusick VA ed. The Hohn Hopkins University Online Mendelian ilheritance in Man#143890
Hypercholesterolemia,Familial (HC:FHC;FH;Hyperlipoproteinemai, Type llA; LDL Receptor
Disorder;LDLR, included).
16. Lyon MF. Gene action in the X-chromosome of the mouse. Nature 1961; 190:372-373.
17. Emery AEH ed. Deford onographs on Molecular Genetics 24 Duchenne Muscular Dystrophy 2nd ed 1993
Oxford Medical Publications
18. Mutirangura a, et al. Multiplex PCR to Detect the Dystrophin Gene Deletion in Thai Patient J Med Assoc
Thai 1995; 78(9)460-465
19. Nussbaum RL and Ledbetter DH, The Fragile X Syndrome. In Scriver CR, Beauded AL, Sly WS and Valle
D. The Metabolic and Molecular Badid of In herited Disease 7ed McGraw-Hill Inc, 1995 P795-810
20. Willard HF. The Sex Chromosomes and X Chromosome Inactioation In Scriver CR. Beaudet AL. Slyws and
Valle D. The Metabolic and Molecular Basis of Inherited Disease 7 ed. McGraw-Hill Inc. 1995 P719-738
21. Mueller RF and Young ID. Emerys Elements of Medical Genetics 9ed 1995 S Chuvchill Lioingstone.

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