GENETICS IN CLINICAL OBSTETRICS AND GYNAECOLOGY Flashcards
Genomics
- preconceptional and prenatal testing
- Newborn screening
- Disease susceptibility
- Screening and diagnosis
- Prognosis and therapeutic decision
- Monitoring disease burden and recurrence
a stretch of nucleotides that code for a
polypeptide
gene
code for the protein that
the gene encodes
Exons
Codons
- Is genetic code
- made of RNA
- Consists of 3 sequential nucleotides
- Total possible number of codons is 64
(because DNA contains 4 nucleotides) - Is degenerate (ie. more than 1 codon
can specify the same amino acid but no
codon specifies more than 1 amino acid)
types of chromosomes
i. Metacentric (i.e. the 2 arms of the chromosome are equal in length)
il. Submetacentric
iii Acrocentric
iv. Telocentric (do not exist in humans)
v. Holocentric (do not exist in humans)
Largest chromosome
chromosome 1
Smallest chromosome
chromosome 22
Colchicine inhibits spindle formation. T/F
T
EDTA inhibits deoxyribonuclease. T/F
T
at metaphase, chromosome is identified by — stain
Giemsa stain
Genetic diseases can be categorized into
three major groups:
- chromosomal disorders
- single gene (monogenic) disorders
- multifactorial disorders
chromosomal abnormalities are subclassified into 2:
- numerical
- structural
numerical chromosomal abnormalities are - and -
- aneuploidy
- polyploidy
the six structural chromosomal abnormalitites are:
- translocation
2 deletion - insertion
- inversion
- rings
- isochromosome
*Aneuploidy refers to
an extra or missing chromosome, such as
–in trisomy 21 (Down syndrome) or
–monosomy 45XO (Turner syndrome)
Polyploidy refers to
numerical chromosome abnormalities in which
there is an addition of an entire complement of haploid chromosomes,
such as in
–triploidy, in which three haploid sets occur (69, XXX or XXY or XYY).
–Tetraploidy-4 haploid sets occuring
Numerical or aneuploid chromosome abnormalities involve either
autosomes or sex chromosomes. T/F
T
Most numerical chromosome abnormalities occur as the result of nondisjunction during meiosis or mitosis in which homologous chromosome pairs fail to disjoin. T/F
T
Nondisjunction occurs most commonly at meiosis 2. T/F
F. meiosis 1
there a strong correlation between increasing
maternal age and incidence of nondisjunction. T/F
T
Down syndrome has 3 copies of chromosome 21. T/F
T
——–% of down syndrome are caused by nondisjunction at gametogenesis
95%
—–% are mosaic for trisomy21
1–3%
—-% of individuals with clinical Down syndrome have a structural rearrangement (Robertsonian translocation)
2–4%
incidence of down syndrome
1:800
incidence of edward’s syndrome
1: 6000
incidence of Patau syndrome
1:15,000
incidence of turner syndrome
1:5000
incidence of klinefelter syndrome
!:1000
incidence of triple x syndrome
!:1000
incidence of xyy syndrome
1:1000
T/F: In human genetics only aberrations arising within germ cells are important
T
Examples of Diseases from deletions
*Cri-du-chat(5p-) syndrome
*DiGeorges Syndrome
*Wilms tomour
*Angelman and Prader-Willis yndrome
chromosome loses a segment because of breakage
deletion
rearrangements of the gene order within a single chromosome due to the incorrect repair of two
breaks
Inversion
centromere is outside inverted region
Paracentric inversion
centromere is within the inverted region
Pericentric inversion
the exchange of chromosomal material between two nonhomologous chromosomes
Translocation
2 types of translocation
- balanced reciprocal translocation
- robertsonian translocation
T/F: Balanced Reciprocal Translocations occur as a result of a mutual and physical exchange of chromosome (genetic) material between homologous chromosomes
F. non homologous chromosomes
T/F: Balanced Reciprocal Translocations cause no problem for mitosis
T
T/F: Balanced Reciprocal Translocations cause no problem for meiosis
F: may result in unequal distribution of chromosomes
incidence of balanced reciprocal translocations
1/11,000
T/F: The carrier of a reciprocal balanced translocation is usually phenotypically normal
T
T/F: balanced reciprocal translocation is associated with advanced paternal age
T
Involves any two acrocentric chromosomes that break near the
centromeres and re-join in a way that results in the long arms(q arms)
fusing at the centromere, forming a single chromosome structure and
loss of the short arms( p arm)
Robertsonian translocation
incidence of robertsonian translocation
1/9000 pregnancies
T/F: An individual with robertsonian translocation is genetically balanced, that is, he or she has two copies of each chromosome
T
T/F: The gametes in robertsonian translocation are balanced
F.
the gametes are at risk to be unbalanced
—-% of Down syndrome have Robertsonian translocation
5%
major congenital abnormality in robertsonian translocation is seen in —%
4%
T/F: numerical abnormalities are not inherited
T. Occur as random events during formation of reproductive cells
T/F: some structural abnormalities are inherited
T. some also occur as random events during formation of reproductive cells or early fetal development
T/F: single gene disorders or mendelian inheritance
T
incidence of single gene disorders
3.6/1000 live births (2% of population)
the probability that a gene will have any phenotypic expression at all
Penetrance
the degree to which the phenotype is expressed
Expressivity
Five basic modes of inheritance for Single-gene
diseases
–Autosomal dominant
–Autosomal recessive
–X-linked dominant
–X-linked recessive
–Mitochondria
in autosomal dominant inheritance affected individuals have a ——-% chance of
transmitting the gene
50% (Inheritance =1:2)
The gene product in autosomal dominant inheritance is commonly —-
non-enzymatic protein
T/F: Autosomal Recessive inheritance is not typically seen in every generation
(NOT possible to trace via Family tree)
T
T/F: females are more affected than males in autosomal recessive diseases
F. Males and female equally affected
T/F: Consanguinity increases risk of offspring
T
The gene product in autosomal recessive inheritance is commonly —–
an enzyme
T/F: incidence of X-linked recessive disorders is seen only in males
F. much higher in males than females
T/F: there’s no father to son transmission in xlinked recessive disorders
T
—-% of daughters of affected males are carriers
100%
what is the % of inheritance in son and daughters of carrier females
50% of sons infected and 50% of daughters carriers
X-linked dominant disorders are seen in only females
F.
males and females affected but females more severely affected
for an affected male in X-linked dominant inheritance, what is the incident of transmission to his sons and daughters?
no male to male transmission
all daughters affected
in X-linked dominant disorders, for an affected female what is the incidence of transmission to sons and daughters
1 in 2 risk to children (M+F)
T/F: In mitochondrial inheritance it is difficult to determine the risk of transmission to offspring
T
T/F: All genes in multifactorial diseases work in the context of environment and behavior
T
T/F: Only single disorders follow a clearly defined pedigree pattern of inheritance “Mendelian Pattern”.
T
T/F: In Mendelian Inheritance, for several diseases the family tree may be conclusive even if accurate diagnosis is not made
T
Essential Components of Genetic Counselling
- History and pedigree construction
- Clinical Examination
- Confirmatory diagnosis
- Calculation of recurrence risk
- Counselling
- Follow-up
ETHICAL PRINCIPLES
- Beneficence
- Autonomy
- Justice
- Non-Maleficence
- Veracity
- Fidelity
maternal serum screening for prenatal diagnosis
fetoprotein, estriol and hcg estimation
amniocentesis for prenatal diagnosis
fetoprotein, acetylcholinesterase, chromosomal analysis, biochemical analysis
CVS for prenatal diagnosis
chromosomal analysis, biochemical analysis, DNA analysis
Fetal blood sampling for prenatal diagnosis
chromosomal analysis, DNA analysis
Invasive methods of prenatal diagnosis
- coelocentesis
- CVS
- Amniocentesis
- cordocentesis
- biopsy from fetal tissue
Non invasive methos of prenatal diagnosis
- cell free fetal DNA
- triple test
- USS
- MRI
amniocentesis is performed in which trimester
2nd
incidence of miscarriage with amniocentesis
1 in 300 - 500
CVS is done in which trimester
2nd
risk of miscarriage with CVS
1 in 300 -500
cordocentesis is also called
PUBS
when can cordocentesis be done
after 18 weeks
what is the risk of miscarriage with cordocentesis
2 in 100 women will miscarry
at what GA should fetal tissue biopsy be done
17 - 20 weeks
T/F: < 1 in 1000 women will get infection with fetal tissue biopsy
T
at what GA should coelocentesis be done
before 10 weeks
the space between the amniotic cavity and uterine cavity
coelomic space
incidence of fetal loss with coelocentesis
0 or < seen in amniocentesis
fetal fraction in maternal blood for cell-free fetal DNA
> 3.5%
T/F: cell-free fetal DNA is affected by gestational age and maternal BMI
T
T/F: High false positive rates with cell-free fetal DNA
F. low
reason for false positives seen with cell-free fetal DNA testing
results confounded by placental mosaicism, chromosomal translocations, uniparental disomy, vanishing twin
T/F: cell-free fetal DNA can detect trisomies 18, 13 and 21
T
triple test meases –,— and –
alpha fetoprotein, hcg and unconjugated estriol
quadruple test measures –,–,– and –
alpha fetoprotein, hcg, unconjugated estriol and inhibin A
T/F: adequate DNA is obtained with one process of PCR examination
F.
Repeat process 30 times to get adequate DNA
T/F: PCR identify specific DNA sequence for gene mutation & prenatal Dx.
at an earlier stage before an embryo transfer in IVF cycle.
T
FISH detects specific DNA sequences in – and– phases of the cell cycle
interphase and metaphase.
T/F: FISH results are available in one week
F. 24-48hrs
T/F: FISH allows detection of big structural rearrangements
F.
FISH Identifies —% clinically relevant abnormalities
80%
read the order of bases (ATGC) in genome of an individual
sequencing
first generation sequencing
sanger sequencing: single gene disorders, 300-1000bp, cost implication
second generation sequencing
- pyrosequencing:
- ion torrent
- illumina sequencing
3rd generation sequencing
pacific biosciences: single molecule real time sequencing, epigenetic studies
4th generation sequencing
nanopore technology
ADVANTAGES OF next generation sequencing
- targeted gene sequencing
- whole genome sequencing: entire nucleotide sequence of the genome
- whole exome/clinical exome sequencing: protein coding regions
examples of multifactorial diseases
Spina bifida, diabetes, and heart disease
examples of X linked dominant diseases
FAIR:
F - (oro) facial syndrome
A - alports
I - incontinenta pigmento
R - resistant rickes (hypophosphatemic)
R - Rett syndrome
examples of X-linked recessive diseases
(Be Wise, Fools GOLD Heeds Silly Hope)
B - Bruton’s agammaglobulinaemia
W - Wilscot aldrich syndrome
F - Fabry’s syndrome
G - G6PD deficiency
O - ocular albinism
L- lesch nyhan syndrome
D - dystrophy (duchenne’s and beckers)
H - hunter’s syndrome
H - haemophilia A and B
examples of autosomal recessive diseases
PASTA CHAWAL
P - phenylketonuria
A - alkaptonuria
S - sickle cell anaemia
Ta - thalasemia
C - cystic fibrosis
H - haemochromatosis
A - alpha AT deficiency
W - wilson disease
A- albinism, adrenal hyperplasia
L - lysosomal and glycogen storage disease
examples of autosomal dominant diseases
Very Powerful DOMINANT Humans
V - von willebrand and von hippel lindau
P - pseudohypoparathyroidism
D - dystrophia myotonica
O - osteogenesis imperfecta and osler weber rendu
M - marfan syndrome
I - intermittent porphyria
N - neurofibromatosis
A - achondroplasia and adult polycystic kidney disease
N - noonan syndrome
T - tuberous sclerosis
H - hypercholesterolaemia, huntington disease, hypertrophic obstructive cardiomyopathy, hereditary spherocytosis, hereditary non polyposis colon ca, hereditary haemorrhagic telangiectasia
