Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
With
Prof. Dr Mohammed Abo El-Asrar
Edited By
El-Azhar Medical students 2012
Genetics INDEX
Total pages = 39
Total time = about 6.5 hours
Lecture number
Pages
1- lecture 28 4 - 9
basics ( page 4 )
inheritance 6 ( Autosomal inheritance 6 )
2- lecture 29 10 - 16
cont. inheritance
( Sex chromosome inheritance 9 + Y - linked inheritance 12 + Co - dominant inheritance 12
+ Intermediated inheritance 13 + Germline mosaicism 13 + mitochondrial inheritance 13
+ Genetic hetero-genicity 14 + Multi factorial inheritance 14 )
Chromosomal aberration ( page 14 )
( Etiology 14 + Mechanisms 14 )
3- lecture 30 17 24
cont. mechanisms ( page 16 )
Classification of chromosomal aberration ( page 18 )
Down syndrome ( page 19 )
4- lecture 31 24 - 29
cont. down ( page 24 )
Trisomy 13 ( page 28 )
Trisomy 18 ( Edward syndrome ) ( page 29 )
anti mongolism = 21 Q ( page 30 )
cri-du-chat-syndrome = 5 P ( page 30 )
turner syndrome ( page 31 )
clinical features of Down on data show ( page 33 )
5- lecture 32 29 - 37
cont. turner ( page 35 )
Klinefelter syndrome ( page 37 )
Page |
2012
:
: : : :
.. .. .. ..
..
Items sub items
.. .. ..
.. .
.. .. .. .
.. .. .. ..
.
.. ( ) -
. /
..
| Page
2012
Genetics
: 1- Inheritance
2- Chromosomal abnormalities
Basics
basics
46 .. .. So, called 23 pairs of chromosomes
23 ) 22 pairs ( autosomal ) + 1 pair ( sex 22 pairs ( ) Called autosomal chromosomes
sex chromosome 1 pair
or XY May be XX
anatomy chromosome DNA mitosis .. meiosis metaphase chromatid by centromere centromere chromosome ) Short arm and long arm( short arm ( .. ) .. P long arm Q chromosomes .. 3
Long , Short & Medium size
chromosome .. X
chromosome ,,,
centromere
centromere .. short and long arm centromere:
1- Metacentric chromosome beside the center
long and long arm
) 2- Centromere in extremities Acro - centric chromosome ( acro means
short arm .... 21, 18, 22 ) called Sub metacentric chromosome ( 3- if between 1 & 2
| Page
2012
| Page
2012
INHERITANCE
1- Autosomal inheritance
- In one pair of autosomal chromosome Same anatomically but different in gene
genes anatomically
( Normal gene with pathological gene medicine ) 3
Normal gene on one and normal gene on other locus 2 identical loci ) genotype ( .. ) 2 identical gene on 2 identical loci ( homozygous
completely normal person clinically .. homozygous genotype
phenotype .. clinical manifestations normal phenotype So, here
2 pathological gene on 2 loci So, genotype homozygous
phenotype diseased
dominant or recessive gene Normal gene in one locus and pathological gene on opposite locus
So, genotype heterozygous
dominant or recessive pathological gene phenotype
* So, if phenotype diseased so pathological gene ( is dominant )
Hetero Homo dominant
* If phenotype normal so, pathological gene ( is recessive )
homo recessive
dominant Or recessive gene hetero
Autosomal dominant inheritance
3 .. pathological gene
.. items
Characters
1 - no sex difference ( as autosomal )
2- may be homo or hetero .
Page |
2012
DD diseased ( phenotype )
Dd also, diseased
.. d ..diseased D
( normal )
So, if any autosomal inheritance at least one of the parents is diseased
Page |
2012
3- gene penetrance :
: gene factor ,,, .. environmental factors
,,, recessive or AD
G6PD deficiency antioxidant
( ) ,,, G6PD
,,, ,,, ,,, ,,, ( )
6 ,,, hemolysis
.. ..
.. gene penetrance
Need environmental factors .. ( )
( ,,, BA) bronchogenic carcinoma
4- illegal son
,,,, ,,, ,,
) AR ( Autosomal recessive gene inherita nce
Characters
items ..
1 - No sex differences
2- the affected person should be homozygous .
- Pathological recessive gene ( r )
:
RR or Rr Or rr
if RR normal
if Rr normal
only rr diseased
| Page
2012
3- so, unaffected persons ( phenotypically norma ) are either genotypically normal or hetero ( carrier )
4- both parents are carrier or one diseased & the othe is carrier .
: .. rr diseased diseased rr may both
) Or morbidity lethal r NB (
rr
hemosiderosis .. ) B- thalassemia major (
gonands ) B thalassemia major complications (
) diseased ( Rr
r consanguinity
) recessive pathological gene more common in cansanguant marriage (
,,,
,,, consanguinity
) ( 1st degree
Called 1st cousin or Second degree .. consanguinity
Called 3rd degree consanguinity Or 2nd cousin Non consanguant marriage ) ( 28
29 28
VS
XY
So, XX - XX - XY - XY
) ( female to male = 1: 1
G6PD pathological gene
,,,
Here father is diseased .. Mother is Normal
So, all daughters carrier
normal sons .. ) Male ( X
carrier genotype .. Normal phenotype ) ( females normal carrier
XY normal person .. ) diseased X ( XX
XX
XX
VS
XY
- XX - XY - XY :
:
1- genotype
( XY ( diseased Males .. ) XX ( carrier females
2- phenotype
All females normal .. 1/2 males diseased
diseased ,,, ,,,,,,
XX
XX
XX
VS
- XY
XY
XY :
:
1- Genotype
All females carrier
2- phenotype
all females normal
.. gene .. generations
) ) ( (
Page |
2012
10
.1
.2
diseased carrier
.3
.4
females common in males G6PD
common in males ,,,
female ..
) homozygous diseased (
1- diseased father & the mother is carrier
carrier diseased 2- diseased mother & farher
diseased diseased XX
VS
XY
3- turner $ :
turner syndrome gene X female ,,, diseased carrier
4- new mutations :
So, carrier One gene .. homozygous .. normal X gene mutation fetus
New mutation in a carrier
5- lyon's theory
lyon's theory ..
XX
- XX : females -
11
Nucleus
.. non functioning
Non functioning
( : ) .. X - chromosome .. .. Barr body pathological gene
.. Nucleus .. pathological genefunctioning
female pathological gene
( : ) X nucleus gene .. X Barr body
gene .. recessive ( dominant ) normal Barr body .. recessive ( dominant ) Barr body
So, lyon's theory say that :
Female may be Genotypically carrier ( XX ) but pathological gene X present on functioning X chromosome so,
phenotypically diseased
male .. female X
,,, male
female X gene gene Males X ,,, Males X - linked dominant
homo or hetero .. common in males females ,,, Barr body )
) Non functioning
12
| Page
2012
A .. B : A - B - AB - or O
BO :
VS
)- AB (AB ) - BO (B
AO
)AO (A
)OO ( O
Rr
13
| Page
2012
8 - Genetic he tero-genicity
differential diagnosis different genotype may cause same phenotype .. ) albinism ( ... albinism albinism
9- Multi factorial inherita nce
risk factor ) ( risk factor gene G6PD .... environmental factors
,,,
Mitochondria head of sperm
ovum Mitochondria in tail only
C hromos omal aber ration
Etiology
etiology
.. germ line mosiacism
1- Old maternal age
abnormality .. 2- May viral infection
,, ) gonadal cells ( Auto immune disease
3- Teratogen drugs
gonadal cells 4- May exposure to irradiation
gonads 5- May transmitted
6- May gene factor
- As fragile X - chromosome
Mechanisms
A - Non disjunction
failure of separation of 2 homologous chromosomes ) ( 95 % commonest : meiosis .. cell division 46 meiosis
Page |
2012
14
st
15
Mechanism
B - Breakage
chromosomes :
Short arm that has 2 regions
- paired chromosome
( another
) acrometacentric
16
| Page
2012
( .. ,,, .. )
Long arm long arm .. 45 46 functionally .. Called balanced translocation carrier
,,, generations
3- Inversion :
.. .. Called inversion " in " ( IN SMALL LETTERS ) genetics
4- ring chromosome :
chromosome short arm .. long arm
( ) .. Called ring chromosome karyotyping C - ISo- chromosome formation :
.. 1st meiotic division .. 23 meiosis 2nd mitosis chromosomes .. fibers chromatid .. 2
chromatid centromere
chromatid
( ( ) )
.. iso chromosome fibers short arm Long arm ..
chromatid .. short arm short arm long Long arm ( ) 2 short ,,, centromere
regions short ).. )Mirror shape iso chromosome
,,,,
17
| Page
2012
Deletion
Ring chromosome
Translocation
Isochromosome
duplication ) 3 1 ( 3 1 region chromosome Page |
2012
18
( .. 35 )
,,, 36 0.5 % Down
3
) So, 39 years 1 % , 43 years 2 % & 45 years 0 % ( Menopause
2- Translocation
Represents 4 % of Down
stem cell testes ovary .. 21 13 short arm 2113 Long arm Translocated .. 21 Long arm 13
Balanced translocation carrier 45 chromosome
) by 1st meiotic devision ( 2 gametes Long arm 21 long .. 13 13
21
19
| Page
2012
.. ..
46
2 of 13 + 2 of 21 + 42 others ..
21 long arm 13
20
| Page
2012
:
: .. 42 others + 2 of 13 + 2 of 21
.. 21 13
C1 & C2
C1 = 21 others + 1 of 21 = 21+1 = 22 chromosomes
C2 = 21 others + 1 of 13 + 1 adhesied ( 13&21 ) = 21+1+1= 23 chromosomes
..
C2 = 21 others + 2 of 13 + 1 of 21
) sperm Ovum ( Other gametes
gametes
) ) testis ( Sperm ( 21 13
) Functionally 46 .. 45 stem cells (
S sperm S = 21 others + 1 of 13 + 1 of 21 = 21 + 1 + 1 = 23 chromsomes
..
: .. ..
: ) (
A1 = 21 others + 1 of 13 + 1 of 21 = 21+1+1=23 chromosomes
A2 = 21 others + 1 adheised ( 13&21 ) = 21+1 = 22 chromosomes
B1 = 21 others + 1 of 13 = 21+1 = 22 chromosomes
B2 = 21 others + 1 of 21 + 1 adhesied ( 13&21 ) = 21+1+1= 23 chromosomes
..
B2 = 21 others + 2 of 21 + 1 of 13
C1 = 21 others + 1 of 21 = 21+1 = 22 chromosomes
C2 = 21 others + 1 of 13 + 1 adhesied ( 13&21 ) = 21+1+1= 23 chromosomes
..
C2 = 21 others + 2 of 13 + 1 of 21
& S = 21 others + 1 of 13 + 1 of 21 = 21 + 1 + 1 = 23 chromsomes
NB. Normal cell ( = N ) = 42 others + 2 of 13 + 2 of 21 = 46 chromosomes
) Z zygoute ( : zygote fertilization 1- S Vs A1 normal
- A1 = 21 others + 1 of 13 + 1 of 21 = 21+1+1=23 chromosomes
- S = 21 others + 1 of 13 + 1 of 21
So, Z = A1 + S = 42 others + 2 of 13 + 2 of 21 = N = 46 chromosomes
Page |
2012
21
..
2- S Vs A2 normal but balanced translocation
- A2 = 21 others + 1 adheised ( 13&21 ) = 21+1 = 22 chromosomes
- S = 21 others + 1 of 13 + 1 of 21
So, Z = 42 others + 1 adheised + 1 of 13 + 1 of 21 = 42+1+1+1 = 45
: zygote .. ) Balanced translocation carrier( 2 .. 21 2 13 2
3- S Vs B1 monosomy 21
- B1 = 21 others + 1 of 13 = 21+1 = 22 chromosomes
- S = 21 others + 1 of 13 + 1 of 21
So, Z = 42 others + 2 of 13 + 1 of 21 = 21+2+1=45 = monosomy 21
4- S Vs B2 trisomoy 21
- B2 = 21 others + 1 of 21 + 1 adhesied ( 13&21 ) = 21+1+1= 23 chromosomes
- S = 21 others + 1 of 13 + 1 of 21
So, Z = 42 others + 2 of 21 + 1 of 13 + 1 adheised = 42+2+1+1=46
: ) Down $ ( trisomy 21 21 3 13 2 (Down contain 46 chromosome But functionally 47 )
5- S Vs C1 monosomy 13
- C1 = 21 others + 1 of 21 = 21+1 = 22 chromosomes
- S = 21 others + 1 of 13 + 1 of 21
So, Z = 42 others + 2 of 21 + 1 of 13 = 42+2+1=45=monosomy 13
6- S Vs C2 trisomy 13
- C2 = 21 others + 1 of 13 + 1 adhesied ( 13&21 ) = 21+1+1= 23 chromosomes
- S = 21 others + 1 of 13 + 1 of 21
So, Z = 42 others + 2 of 13 + 1 adheised + 1 of 21 = 46
: trisomy 13 13 3 21 2 (contain 46 chromosome But functionally 47 )
: .. ..
,,,
Zygote formation 2 of 13 and 1 of 21 Monosomy of 21
,,,
2 of 13 and 3 of 21 Trisomy of 21 (Down contain 46 chromosome But functionally 47
Page |
2012
22
)
46 functionally 45 non disjunction 46 47
,,,
Zygote 2 of 21 + 2 of 13
2 ( ) Balanced translocation carrier zygote
,,,
.. 2 of 21 + 2 of 13 Normal
,,
- zygote 2 of 21 + 3 of 13 Trisomy 13
,,,
- Zygote 2 of 21 + 1 of 13 Monosomy of 13
21 ( balanced translocation carrier ) other chromosome
:
1- 25 % Down
2- 25 % balanced translocation carrier
3- 25 % normal
4- 25 % trisomy of the chromosome
( monosomy 13 21 ) early abortion
.. % 25 Down .. % 33 trisomy
: -1 Other trisomy25 %
-2 33 %
survey ) 21 adhese to other chromosome( balanced translocation carrier Down ) As actual risk incidence( 10 - 15 %
25 %
Down anomalies () Early abortion balanced translocation carrier survey 2 - 5 %
25 %
sperm Down .. extra chromosome motility sperm fertilization
" "
23
| Page
2012
,,,
.. balanced translocation carrier
,,, .. ) 2 ( translocation ,,,
No abnormality could be detected
General clinical presentation of any autosomal chrosomal disorders
1- Mental retardation
) ( idiot ,,, degrees sphincter control 2- Growth retardation
history .. 3- All brain sized microcephaly
All in head circumference
4- May multiple congenital anomalies
Multiple anomaly .. stress disorder ..
a- Eye
24
Cataract or glaucoma
d- Hernias
Umblical or inguinal
Hypotonia
e- Genital anomalies
d- Limb anomalies
Poly dactyl ( )
1.
2.
GIT anomalies
Pyloric stenosis
3.
Renal anomalies : as
Polycystic kidney
4.
Anomalies in thyroid
1- Associated anomalies as :
Page |
2012
25
Renal failure
26
Called complete simian crease proximal distal Normal ) ( another crease complete simian crease partial flexion
Called incomplete Simian crease
B - brachy dactyl
C - rudimentary middle phalanx of little finger .
rudimentary middle phalanx 2 crease only Little finger D incline dactyl
Called inclino dactyl Investigations
1 In all genetics Karyotyping
clinical diagnosis Down Karyotyping cytogenic type of Down non disjunction ) 21 3 ( 47 -
translocation 46 -
mosaic pattern 47 46 -
2 Chest X ray
,,,,
Down X ray chest and heart
) ( congenital heart disease -1
Pneumonia chest infection -2
) If associated with leukemia( enlarged mediastinal lymph nodes -3
retro sternal goiter ... May associated Hashimoto's thyroiditis
.. -4
27
Treatment
No thing .. Only special care and supportive treatment
What about future pregnancy ???
,,,
Karyotyping
.. ) non disjunction ( 47 ) 35 ( Down
trophoblastic biopsy .. Down
-1
,,, .. ) ( amniocentesis ) 6 - 8 (
12 induced abortion ( abortion Down
)
abortion .. 6 - 8 trophbalstic
abortion 13 14 .. amniocentesis -2
contraceptive ,,,
trohpobalastic ,,, ) ( extra chromosome 46 karyotyping Non disjunction .. other 21
) (tubal ligation .. 21 21
Tris omy 13
karyotyping amniotic fluid NB
3 13 karyotyping ,,,
Enumerate autosomal chromosomal aberration and discuss one of them ??
Down Most common
Types
As Down with same risk factors ( as Down (
Clinical pictures
1.
Mental retardation
2.
Growth retardation
3.
Microcephaly
Page |
2012
28
4.
29
Down hypo
2- Prominent occiput
3- Ears
Low set ears .. Down
tragus .. Lateral angle of the eye .. ) chromosomal ( Down ear
malformation + Low set ear 18 4- Hands Clinched fist
Hypertonia
Overlapped palm middle ring
5- Rocker bottom heel
Investigations and treatment
As Down
cri-du-chat -sy ndrome = 5 P Deletion of short arm of 5th chromosome
Called cri-du-chat-syndrome
Clinical Manifestations
3 +
1- Round face
2- Marked hypertelorism
3- Cat like cry
due to laryngeal hypoplasia
Investigations
Karyotyping
Treatment
Supportive treatment
a nti mongolism
= 21 Q -
30
Page |
2012
31
out side mid clavicular line at mid clavicular line Nipple So, wide spaced nipple
3- Congenital heart disease :
coarctation of Aorta
4- wide carrying angle :
radius Ulna .. radius and ulna forearm
Carrying angle trunk .. full supination
radius
So, wide carrying angle
elbow .. pronation
5- genreralized non biting odema at birth
sonar Intra uterine lymphatic .. non biting .. generalized edema
lymphatic hypoplasia 6- triangular face
forehead chin triangular face 7- No menstruation No 2ry sexual character
15 -13 infertile fibrotic ovary .. ovary sonar
turner
1- deletion of short arm of one of X chromosome ( 46 XX P - )
Barr body buccal smear ) 46 XX P - ( deleted X short arm
deletion of short arm of one of X chromosome
ovarian function turner - normal menstruation , Normal 2ry sexual character & normal menopause
Page |
2012
long arm -
32
3- mosaic turner :
) ( mosaic turner ... X 45 .. Menopause
,,,
turner
turner )Deletion of short arm only( XX P - mosaic
Investigations
1.
2.
3.
4.
5.
Diagnostic karyotyping
Treatment
33
3- Brachycephaly ( occiput flat )
4- Eye :
- depressed nasal bridge and medial epicanthus So, apparent convergent squint.
- upward slanting of the eye
) ( medial angle Lateral angle .. Down
- Micro ophthalmia
- Iris brush field iris
with line of demarcation Iris
5- Scrotal tongue means prominent rogue on the tongue
) Scrotum tongue (
.. .. ) ( micrognathia
tongue suckling ..
hypertrophy of papillae of tongue from prolonged suckling
6- In hands
- Simian crease
- Inclino dactyl
- Brachydactyl
7- wide space between big toe and other toes:
wide space between big toe and other toes ..
8- On sole :
deep grove opposite space between big and other toes
9- Acrobatic sign due to severe hypotonia
) 1886 Down NB (
Trisomy 13 also, on data show
- Marked micro ophthamia
- May single eye
Nonann syndrome
1963 - turner -
32 31
Page |
2012
34
,,,
.. ,,, female Short stature, webbing of neck + skeletal deformity
: turner syndrome
,,, ,,
:
,, ,, ..
,, turner
mosaic turner
46 XX P -
( )
gametes .. 1st meiotic 23 gamete X ( ) 2nd meiotic division mitosis fibers
fibers .. short arm Long arm
2 gametes short Long short arm short Long arm long fertilization gametes ( X )
turner phenotype .. 1 short arm 2 short arms2 long arms
So,
) 1- if gamete with 2 short arm fertilized by normal gamete ( 1 short and 1 long
3 short arm + 1 long ..
2 short 4 .. 3 short 6 So, tall female
Long arm .. ) Degenerated ovary no 2ry sexual characters (Fibrotic ovary
) 2- or gamete with 2 long arms fertilized by nomral gamete ( normal gamete contain 1 long + 1 short
So, net result 1 short + 3 long
webbing coarctation skeletal deformity
35
| Page
2012
) ( + So, appearance of 2ry sexual character 3 long ) Long fertility age( menopause
) long .. support 3 ovary .. ovary degeneration (
: turner turner
Due to iso chromosome of the long arm of the X chromosome
) ( turner features .. turner
Called Nonann syndrome
turner Nonann
Etiology
turner
nonann
chromosomal disorder
Sex
Must be female
male or female
Mentalitity
normal
variable degrees of MR
Fertility
fertile
Karyotyping
Abnormal
normal
MR Nonann
,,,
severe MR .. mild MR ,,, :
illegal pregnancy
Intra uterine criteria of turner
Generalized edema
heart failure Hydrocephalus edema After delivery
1.
Triangular face
2.
Coarctation of Aorta
3.
Webbing in neck
4.
Page |
2012
36
Klinefelter sy ndrome
2 X + 1 Y So, 47 XXY
Male as there is Y
Y 2 X 2 ) 6( So here , tall stature
- has 2 X so, More ovarian genes Cause atrophy of testis ( degeneration of gonadal cells )
) short .. X long arm ovarian gene (
- No somatic deformities
..
..
1- No 2ry sexuall characters :
Other sex testosterone .. ) .. (
) (
2- fat with female distribution of fat
fat muscle Klinlfelter .. fat muscle
and
3- Feminine behaviour
) same sex ( Homosexual 30 %
Investigations
1.
2.
testosterone level
3.
FSH & LH
4.
Fibrotic testis
) ovary (
5.
Karyotyping 47 XXY
) X 2 ( 48 XXXY .. calssic 47 XXY
But only emotionally affected ) ( normal mentality 47 XXY
female behaviour .. -
37
,, Klinfelter Mosaic
Treatment
38
| Page
2012
www.facebook.com/dr.tafreegh
39
| Page
2012