Transcript Cytogenetics and multifactorial inheritance

Cytogenetics
Dr Alice S Chau
Cytogenetics
= Study of chromosomes and their abnormalities
Karyotypes
 Display of chromosomes in the order according to
length and shape
 The latter depends on the position of the centromere
at the metaphase:
1. Metacentric
2. Submetacentric
3. acrocentric
Different chromosome karyotypes
Metacentric
Submetacentric
Acrocentric
Short
Arm p
satellite
Long
Arm q
A normal female karyotype – 46, XX
Disorders of chromosomes
Normal female karyotype = 46, XX
Normal male karyoptye = 46, XY
(1) Numerical abnormalities
Aneuploids – failure of separation of paired
chromosomes at cell division
(a) Trisomy e.g. (+21)
(b) Monosomy e.g. (-X)
(c) Triploidy, Tetraploidy e.g. (69, 92 chromosomes)
Disorders of chromosomes
(2) Structural Disorders
(a)Translocation – (t) : reciprocal exchange of
chromosome segment
(b) Deletion – (del) : loss of genetic material
(c) Duplication – (dup) : extra copy of
chromosome region
(d) Isochromosome – (i) : duplication of one arm
and lack of others
(e) Ring chromosome – (r) : abnormal repair at
distal segment to form a ring
Chromosome abnormalities
(1) Autosomal syndromes
 Trisomy 21 (Down syndrome) 47, XY, +21
 Trisomy 18 (Edwards syndrome) 47, XX, +18
 Trisomy 13 (Patau syndrome) 47, XX, +13
 Deletion #15 (Prader Willi syndrome) 46, XX, del(15q)
(2) Sex chromosome abnormalities
 Turner syndrome (45, X)
 Klinefelter syndrome (47, XXY)
 Fragile-X syndrome
Relationship of maternal age on
risk of Down’s syndrome
Maternal age
risk
20 years
1 in 1,500
30 years
1 in 900
35 years
1 in 400
40 years
1 in 100
45 years
1 in 30
Recurrent risk of Down’s syndrome
patient
mother
father
Chance of
recurrence (%)
Carrier
N
Carrier
N
Carrier
N
Normal
C
Normal
C
Normal
C
10-15
5
10-15
5
100
100
Trisomy 21
N
N
1
Translocation or
mosaic
N
N
small
D/G translocation
21/22 translocation
21/21 translocation
Multifactorial Inheritance
Dr Alice S Chau
Multifactorial inheritance
 Caused
by combination effects of many “genes” and
“environmental” factors
Environmental
Genetic
Infection
Radiological
Chemical
Cystic fibrosis
Haemophilia
Marfan syndrome
Examples: body height, intelligence, cleft lip and/or
palate, congenital heart disease, coronary heart
disease, diabetes mellitus, cancers, schizophrenia &
neural tube defect
Incidence of genetic disorders
Chromosomal abnormalities
Single gene mutation
Familial
Multifactorial inheritance
Others & unknown cause
10%
3%
14%
23%
50%
Recurrent risks in genetic disorders
 Single
gene disorders
– Autosomal dominant
50%
– Autosomal recessive
25%
 Multifactorial inheritance
– “empirical risk” – based on direct observation of
data, on a large series of affected families, thus
calculating the percentage
e.g. cleft lip & palate
General population = 1/1,000
First degree relative = 4%
Second degree relative = 7 per thousand
Genes in common
Genes in common
Monozygotic twins
Parent-child, sibling, dizygotic twins
Grandparents, uncle, aunt
First cousin
Second cousin
1
1/2
1/4
1/8
1/32
Neural tube defect
 Generally
about 3% of recurrent risk
Cleft lip & palate

Risk of recurrence:
In unilateral cleft lip – 2.7%
In bilateral cleft lip – 5.4%
Coronary Heart Disease (1)
Genetic factors:
1. Lipid metabolism
(a)Familial hypercholesterolaemia (A.D.)
(b)Familiam combined hyperlipidaemia (A.D.)
2. Lipoprotein
(a) Apolipoprotein E
(b) Lipoprotein A
(c)Angiotensin I converting enzyme
Environmental factors:
diabetes mellitus, hypertension, obesity, smoking,
exercise, dietary, menopausal women
Major features in type I & type II
DM
> 40 years
Insulin production
Type I DM (insulin
dependent)
< 40 years old (HLADR3 or DR4 antigens)
None
Insulin resistance
-
+
Auto-immunity
+
-
Sibs recurrence
1-6%
10-15%
M-Z twin concordance
0.35-0.5
0.9
Obesity
Uncommon
Common, with
family history
Onset
Type II DM
partial
Cancers
(i) Colo-rectal cancer
a) Adenomatous polyposis coli (APC, familial
polyposes)
a tumour suppressor gene, at 5q21 deletion,
related to 85% of C-R cancer, due to mutation
b) Hereditary nonpolyposis colon cancer
(HNPCC)
genes in DNA mis-match repair, at 2q15-21,
related to 1-5% of C-R cancer, due to genomic
instability
Cancers
(ii) Breast cancer
Several gene mutations are known in DNA repair e.g.
BRCA1 at 17q21 and BRCA2 at 13q12
(iii) Ovarian cancer
Mutation gene of BRCA1 at 17q21
(iv) Prostate cancer
Identified linked polymorphism on 1q
Cancers
(v) Retinoblastoma
40% are familial and inherited as autosomal
dominant
Deletion gene at RB1 at 13q14
(vi) Cancer cytogenetics
“Philadelphia chromosome” in chronic myeloid
leukaemia (ph1)
Reciprocal translocation between chromosome 9 and
22 or t(9;22)
Schizophrenia
 No
specific genes have been cloned but the gene
“SCZD2” at 11q might predispose to schizophrenia
& marked familial aggregation has been observed
 When one affected parent is diagnosed, the risk for
offspring is 8 to 10% (i.e. 10 times higher than
general population)
 If one affected parent and one sib affected, the risk
for next child is 14% recurrence
 Environmental factors – poor socio-economic
status, child born in winter season