genetics Flashcards
how many pairs of chromosomes does a human have?
structure
23
short arm (p) & long arm (q)
joined at centromere
what is a chromosome called when:
i) arms are same length
ii) one arm is longer than other
iii) centromere is situated at top of chromosome
i) metacentric
ii) submetacentric
iii) acrocentric
name given to:
i) 1st 22 pairs of chromosomes
ii) 23 pair of chromosomes
i) autosomes
ii) sex chromosomes
what is a gene?
How many genes are there in human genome?
a specific sequence of DNA that carries the instructions for the construction of a protein
approx 20,000
what is meiosis?
what are the 2 division cycles in meiosis called?
division of germ cells to produce ova or sperm
meiosis I
meiosis II
what happens during meiosis I?
- chromosomes duplicate
- recombination = homologous chromosomes align and reciprocal exchange of genetic material occurs between homologous but nonidentical chromatids
- diploid number of chromosomes is reduced to half number
what happens during meiosis II?
splitting of sister chromatids
(like mitosis but no additional replication)
in female meiosis how many of the 4 daughter cells survive?
only 1
(all 4 survive in male meiosisis)
what is aneuploidy?
abnormality in number of chromosomes i.e. chromosomes are not haploid
what happens in non-disjunction?
what increases risk of non-discjunction?
pairs of homologous chromosomes at **meiosis I **or sister chromatids during mitosis anaphase do not separate so both chromosomes are passed onto 1 daughter cell
therefore:
- 1 daughter cell has 3 chromosomes (trisomy)
- 1 daughter cell is missing 1 chromosome (monosomy)
advanced maternal age
examples of non-disjunction:
Down Sydrome (trisomy 21)
Edward’s syndrome (trisomy 18)
Patau syndrome (trisomy 13)
^^ order above = most to least common trisomies
Klinefelter Syndrome (47, XXY)
Turner syndrome (45,X) - most common monosomy identified at birth
Down syndrome
i. mutation
ii.clinical features
nondisjunction in 95% (other causes include Robertsonian translocation)
characteristic facial features -upslanting palpebral fissures, epicanthic folds, flat midface, brachycephaly (short anterior-posterior diameter of cranium)
moderate- severe learning difficulties (100%)
cardiac problems (40-50%, VSD, ASD, AVSD)
dementia (10-15%)
ALL
Edward’s syndrome
i. which chromosome is affected
ii. what’s the issue
iii. clinical features
poor prenatal/ postnatal outcomes
i. trisomy 18
ii.
meiotic dysjunction
unbalanced Robertsonian translocations (less common)
iii.
survival - usually <1 year
Profound learning difficulties (100%)
Congenital heart disease (90%, commonly VSD)
Facial clefts
Spina bifida
Clenched hands
Rocker-bottom feet
Patau syndrome
i. chromosome affected
ii. genetic cause
iii. clinical features
i. trisomy 13
ii. 90% nondysjunction of chromosome 13 (majority of these during maternal meiosis - rest = due to unbalanced translocations (primarily Robertsonian translocations)
iii.
highest rate of spontaneous pregnancy loss of all the trisomies
Profound learning difficulties (100%)
Holoprosencephaly (60–70%) = when brain doesn’t separate into 2 hemispheres properly
Scalp defects
Cleft lip/palate (60–70%)
Microphthalmia/anophthalmia (60–70%)
Congenital heart disease (80%, VSD, ASD)
Postaxial polydactyly (60–70%)
Omphalocele
Renal anomalies
Klinefelter syndrome
i. affected genes
ii. clinical features
i. additional sex chromosome 47 XXY
ii. Slightly decreased IQ but within the normal range
Tall stature
feminine fat distribution
small testes
Infertility
Transient gynaecomastia
Klinefelter dx:
not usually dx unless incidental finding during:
prenatally
during chorionic villus sampling (CVS) or amniocentesis or in adulthood during infertility investigations
does not cause increase nuchal translucency so not ID on scan
i. hormonal changes in Klinefelter’s:
ii. incidence of Klinefelters
hormonal imbalances
FSH, LH ^^
estradiol ^^
SHBG^^ (sex hormone binding globulin)
testosterone vv
ii. 1 in 650 males
triple X syndrome clinical features:
Slightly decreased IQ but within the normal range
Tall stature
Normal fertility
usual only found incidentally
XYY syndrome clincial features:
Slightly decreased IQ (within the normal range)
Tall stature after puberty
Behavioural problems
Turner syndrome
i. common antenatal feature which prevents survival to term
ii. which finding on USS would make you consider this as dx
iii. clinical features
45,X
i. usually do not survive to term due to hydrops fetalis
ii. nuchal translucency >4mm
iii. primary amenorrhoea, delayed puberty
Turner syndrome
i. clinical features
ii. rx:
- to promote puberty
- to prevent osteoporosis
i. amenorrhoea (may have spontaneous menstruation due to mosaicism)
delayed puberty
short stature
webbing of neck
cubitus valgus (angling out of forearm at elbow)
widely spaced nipples
cardiac abnormalities (most commonly bicuspid aortic valve)
renal abnormalities
most common cause of gonadal dysgenesis
ii. - low dose ostrogen to promote puberty
- LT hormone replacement to prevent osteoporosis
what are reciprocal translocations?
Chromosome rearrangements involving the transfer of genetic material between two nonhomologous chromosomes
most common translocation in humans
t(11; 22)(q 23; q 11)
involves chromosome 11 and 22
what happens in Robertsonian translocation?
chromosome rearrangement that involves fusion of the long arms of two acrocentric chromosomes and loss of their short arms.
The genes contained on the short arms are represented elsewhere and so their loss does not result in any phenotypic effect of acrocentric chromosomes.
which 5 chromosomes can Robertsonian translocation affect?
only the acrocentric ones!!
13, 14, 15, 21, 22
most common Robertsonian translocations (2)
rob (13q; 14q)
involves fusion of chromosome 13 to chromosome 14
rob(14q; 21q)
involves fusion of chromosome 14 to chromosome 21
what is impriting?
(in context of Robertsonian translocation)
which 2 chromosomes are imprinted genes found on?
process by which one parental allele is preferentially silenced according to its parental origin.
14 & 15
what is UPD?
which chromosomes can it affect?
uni-parental disomy …. p 277
again only in with chromosome 14 & 15
outcome & clinical features of
i. maternal UPD 14
ii. paternal UPD 14
i. survive to term
–> small, learning difficulties, hypotonia, relative marocephaly
ii. spontaneous miscarriage
–> (if survive to term) profound LD, feeding diffiuclties, joint contractures
outcome of:
i. paternal UPD15
ii. maternal UPD 15
i. Angelman syndrome
ii. Prader-Willi syndrome
Angelman syndrome
i. cause
ii. clinical features
i. paternal UPD 15
ii. severe learning difficulties
characteristic facial
appearance
ataxic gait
Prader-Willi syndrome
i. cause
ii. clinical features
i. maternal UPD 15
ii. severe learning difficulties
poor feeders in neonatal period, then insatiable appetite and overweight
hypotonic
short stature
what are chromosomal microdeletions?
how are these usually picked up?
chromosomal deletions that are too small to be detected by light microscopy using conventional cytogenetic methods
microarray aCGH
common microdeletion syndromes:
5p15 (cri du chat)
7q11 (Williams)
22q11 (DiGeorge)
Cri du chat
i. mutation
ii. clinical features
5p15 deletion
Severe learning difficulties
Characteristic cat-like cry
Characteristic facial appearance with bitemporal narrowing, hypertelorism (wide distance between eyes)
and downslanted palpebral fissures
Williams syndrome
i. mutation
ii. clinical features
7q11
Mild to severe learning difficulties
Cardiac problems, particularly supravalvular aortic/pulmonary stenosis
Renal artery stenosis
Characteristic facial appearance with short upturned nose, long philtrum, wide mouth,
periorbital fullness
‘Cocktail party personality’ (chatty, interactive behaviour)
DiGeorge syndrome
i. mutation
ii. other names
iii. clinical features
22q11 deletion
velocardiofacial
Shprintzen
C- cardiac anomalies (most commonly tetralogy of Fallot, VSD, interrupted aortic arch)
A - abnormal facies
(tubular nose, narrow palpebral fissures
and simple ears)
T - t-immune cell disorder
C- cleft palate
H - hypocalcaemia
22 - variable deletion on chromosome 22
Mild to moderate learning difficulties
+
Short stature
Psychiatric disorders
Renal anomalies
what are missense mutations?
single-base substitutions that have occurred in a coding, critical region of the gene.
what is a frameshift mutation?
one or more bases
(but not a multiple of three) are inserted or deleted from
the usual genetic sequence so disrupting the normal
reading frame
eventually a new stop codon will be generated resulting in abnormal protein being prematurely truncated
what are nonsense mutations?
a single-base substitution that generates a premature stop codon resulting in a truncated protein
what do both nonsense and frameshift mutations produce?
what are they thus both collectively called?
truncated proteins
truncating mutations
what is splicing?
what are splice mutations?
removal of introns from primary transcript
mutations that affect nucleotides at the splice site (junction between introns and extrons)
what are exon deletions?
occur when 1 or more exons are deleted in a process that does not constitute an alternative splicing event
what causes triplet repeat expansions?
examples of triplet repeat conditions? (3)
important feature in these conditions? (3)
extensive duplication of a single codon. If this goes beyond a certain threshold you get an abnormal phenotype
fragile X syndrome
Huntingdon’s
mytonic dystrophies
- variability in phenotype
- anticipation (progression in triplet repeat size and phenotype severity as repeat is passed onto next generation)
- parent of origin effect (repeat may expand more if passed on by mother than father)
4 patterns of inheritance for genes on single locus:
autosomal dominant
autosomal recessive
X-linked dominant
X-linked recessive
common autosomal dominant conditions & their genes:
tuberous sclerosis (TSC 1/TSC2)
Marfans (fibrillin 1)
neurofibromatosis type 1 (NF 1)
breast/ ovarian cancer susceptibility (BRCA1/BRCA2)
HNPCC (MLH)
Huntington’s disease (Huntingdin)
autosomal dominant polycycstic kidney disease (PKD1/PKD2)
achondroplasia (FGFR3)
tuberous sclerosis
i. affected gene
ii. inheritance
iii. clinical features
iv. which chromosome is mutation on
i. TSC1/TSC2
ii. AD
iii.Multisystem disorder characterised by:
- cutaneous (angiofibromata, hypomelanotic
macules, shagreen patches)
- neurological (brain hamartomas causing seizures)
- renal (angiomyolipomata)
should be strongly suspected prenatally if
cardiac rhabdomyosarcomas are identified
iv. chromosome 9 or 16
Marfan syndrome
i. affected gene
ii. inheritance
iii. clinical features
i. fibrillin I
ii. AD (25% of cases are de novo i.e. not inheritted, v occassionally gene is also recessive?!)
iii.Tall stature, arm span to height ratio >1.05, long fingers, dolicocephaly, aortic
dilatation and other cardiac anomalies
neurofibromatosis type I
i. affected gene
ii. inheritance
iii. clinical features
i. NF1
ii. AD
iii. Combination of cafe-au-lait ´ spots, neurofibromata, axillary and inguinal freckling and
optic glioma
breast/ ovarian cancer susceptibility
i. affected gene
ii. inheritance
iii. clinical features
i. BRCA1/ BRCA2
ii. AD
iii.
BRCA1
60-90% breast ca
40-60% ovarian ca
BRCA2
45-80% breast ca
10-30% ovarian ca
HNPCC
i. affected gene
ii. inheritance
iii. clinical features
i. MLH
ii. AD
iii. Inherited predisposition to the development of colon and other cancers including
endometrial, gastric and ovarian
Huntingdon’s disease
i. affected gene
ii. inheritance
iii. clinical features
i. Huntingdin
ii. AD
iii. Condition characterised by progressive neurological deterioration with dementia,
psychiatric disturbance and movement disorder
Autosomal dominant
polycystic kidney disease
i. affected gene
ii. inheritance
iii. clinical features
i. PKD1/ PKD2
ii. AD
iii. Systemic disorder with cysts in the kidneys, liver, pancreas and spleen and
cardiovascular anomalies including intracranial aneurysms and mitral valve prolapse
achondroplasia
i. affected gene
ii. inheritance
iii. clinical features
i. FGFR3
ii. AD
iii. Condition characterised by disproportionate short stature with rhizomelic (proximal)
shortening and relative macrocephaly
if 2 carriers of autosomal recessive gene have children what is the chance of:
i child being affected?
ii child being carrier
1 in 4
2 in 4
common autosomal recessive conditions (& affected gene) :
cystic fibroisis (CFTR)
Spinal muscular atrophy (SMN)
Tay–Sachs disease (HEXA)
Haemochromatosis (HFE)
α1-Antitrypsin deficiency (SERPINA1)
Congenital adrenal hyperplasia due
to 21-hydroxylase deficiency (CYP21A2)
cystic fibrosis
i. affected gene
ii. inheritance
iii. features
i. CFTR
ii. autosomal recessive
iii.chronic pulmonary disease exocrine pancreatic dysfunction
male infertility (absence of vas deferens)
In Caucasian population:
i. what proportion is a CF carrier?
ii. what is the chance of a couple having a child with cystic fibrosis?
i. 1 in 20 to 1 in 25
ii. 1 in 400
spinal muscular atrophy
i. affected gene
ii. inheritance
iii. features
i. SMN
ii. autosomal recessive
iii.Characterised by symmetrical proximal muscle weakness; life expectancy
ranges from infancy to adulthood depending upon the type of spinal muscular
atrophy
Tay-Sachs disease
i. affected gene
ii. inheritance
iii. features
i. HEXA
ii. autosomal recessive
iii. A GM2 gangliosidosis characterised by a ‘cherry-red spot’ on the retina and
deteriorating motor and cognitive abilities
haemachromatosis
i. affected gene
ii. inheritance
iii. features
i. HFE
ii. autosomal recessive
iii. Excess absorption of iron with deposition in liver, pancreas and skin leading
to cirrhosis, diabetes mellitus and bronzed appearance of skin
α1-Antitrypsin deficiency
i. affected gene
ii. inheritance
iii. features
i. SERPINA1
ii. autosomal recessive
iii.1 α1-Antitrypsin is a proteinase inhibitor that protects the lungs from elastase;
without α1-antitrypsin individuals will develop emphysema at a young age; they
may also develop cirrhosis owing to a direct effect of the abnormal
α1-antitrypsin on the hepatocytes
Congenital adrenal hyperplasia due
to 21-hydroxylase deficiency
i. affected gene
ii. inheritance
iii. features
i. CYP21A2
ii. autosomal recessive
iii. 2 Attributable to abrogation of 21-hydroxylase, required for the synthesis
of cortisol; associated with female virilisation and abnormal puberty (precocious
in boys) with or without salt wasting
X linked recessive inheritance characteristics
if recessive mutation is on X chromosome males will be affected
- only males are affected (if for some reasons females are affected they will have a milder phenotype
- there is no male to male transmission
- condition may appear to skip conditions
examples of X-linked recessive conditions & affected gene:
Duchenne muscular (dystrophin)
Haemophilia A (factor VIII gene)
ocular albinism (GPR143)
X-linked adrenoleucodystrophy (ABCD1)
Fragile X Syndrome (FMR 1)
Duchenne muscular dystrophy:
i. affected gene
ii. inheritance
iii. features
i. dystrophin
ii. X-linked recessive
iii. delayed motor development
Progressive myopathy affecting proximal muscles
causes early loss of ambulation and
death in the third decade owing to respiratory failure
pseudohypertrophy of calf muscels
waddling gait
cardiomyopathy (dilated)
haemophilia A
i. affected gene
ii. inheritance
iii. features
i. factor VIII gene
ii. X-linked recessive
iii. Attributable to deficiency of factor VIII, an important component of the clotting cascade;
affected male individuals have abnormal clotting, with severe haemophilia A leading to
spontaneous joint and muscle bleeding
occular albinism
i. affected gene
ii. inheritance
iii. features
i. GPR 143
ii. X-linked recessive
iii. Hypopigmentation of iris and retina; associated with poor visual acuity, nystagmus,
strabismus and abnormal decussation of the optic nerves
X-linked adrenoleucodystrophy
i. affected gene
ii. inheritance
iii. features
i. ABCD 1
ii. X-linked recessive
iii. Accumulation of very-long-chain fatty acids in the adrenal glands and brain; results in
progressive cognitive deterioration and adrenal failure
Fragile X syndrome
i. affected gene
ii. inheritance
iii. features
i. FMR 1
ii. X-linked recessive
iii.Caused by expansion of a CGG repeat; results in learning difficulties and characteristic
facial appearance
X-linked dominant inheritance features:
- manifests v v severely in male fetuses resulting in loss of pregnancy or early neonatal death
thus mainly in females
X-linked dominant conditions & affected gene
Incontinentia pigmenti (NEMO)
Rett syndrome (MECP2)
Incontinentia pigmenti
i. affected gene
ii. inheritance
iii. features
i. NEMO
ii. x-linked dominant
iii. Initially presents as blistering lesions following Blaschko lines; these later become
hyperpigmented and eventually appear as atrophic streaks
Rett syndrome:
i. affected gene
ii. inheritance
iii. features
i. MECP 2
ii. x-linked recessive
iii. Associated with cognitive regression and severe learning difficulties; other characteristic features
include hand wringing and stereotypical movements
examples of conditions displaying mitochondrial inheritance:
MELAS (mitochondrial encephelomyelopathy with lactic acidosis and stroke-like symptoms)
MERRF (myoclonic epilepsy with ragged red fibres)
Leigh’s disease Subacute necrotising encephelomyelopathy
which 2 screening tests are routinely offered and at what gestation?
- nuchal translucency (11-14 weeks)
= sonographic appearance of subcutaneous fluid at back of foetal neck - amniocentesis (15-20 weeks)
which maternal factor makes NIPT (non-invasive prenatal testing) less accurate?
maternal obesity - lowers % of free foetal DNA
associations of thickened nuchal translucency?
Noonan’s
chromosomal trisomy
???p 283
what is the combined test (in foetal abnormality screening)?
uses info from nuchal translucency scan + 2 serum biochemical markers:
PAPP-A
h β-hCG
what is detection rate of trisomy by:
i. NT scanning alone
ii. combined testing
- 70-75% (false positive rate 5%)
- near 90%
what are cffDNA tests?
what are they used for used for:
circulating free foetal DNA (free foetal DNA is released by apoptotic cells in the placenta - therefore its cells are representative of nuclear content of cells in developing foetus
determining sex
rhesus D blood typing
detection of trisomy 13, 18, 21
chorionic villus sampling:
i. earliest gestation it’s performed at
ii. what are the 2 layers of the chorionic villus?
i. 11 weeks
ii. aspiration of placental tissue
chorionic villus has 2 cell layers:
outer = cytotrophoblast (rapidly dividing and invading layer)
inner= mesenchymal core
how long does it take to get CVS results from
i. outer cytotrophoblastic layer
ii. inner mesenchymal core
which layer is seen as more representative?
i. 1-2 days
ii. 1-3 weeks
core (as outer layer is established earlier) - therefore if abnormal cytotrophoblastic result must wait for mesenchymal result)
what is confined placental mosacisism?
what % CVS samples is this seen in?
where chromosomal abnormality is present in placenta but not foetal tissue
1.5%
amniocentesis
i. gestation performed at
ii. which foetal organs are the amiocytes derrived from?
iii. how long after procedure are cultured cells from amiocentesis available to harvest?
i. after 15 weeks
ii. skin, urinary and GIT
iii. 1-3 weeks
what are the miscarriage rate after CVS/ amniocentesis?
advantage of CVS>amniocentesis?
approx 1%
results more rapidly availably
i. what is cordocentesis?
ii. from what gestation can this be done?
iii. associated miscarriage rates?
i. sampling of foetal from umbillical vein
ii. 18 weeks
iii. 1-2%
what is cordocentesis used to asses?
anaemia
prenatal infection
FISH (fluorescent in situ hybridisation)
i. uses
ii. advantages
iii. disdvantages
i. rapid aneuploidy detection
evaluation of unbalanced translocations
ii. A good technique for investigating
predictable unbalanced
chromosome rearrangement
iii. spenny
labour intensive
QF-PCR (quantitatvie fluorescence PCR)
i. uses
ii. advantages
iii. disadvantages
i. rapid aneuploidy detection
ii. rapid results
cheap
iii. Will usually only identify abnormal
dosage involving chromosomes 13,
18 or 21
MLPA (Multiplex ligation-dependent probe amplification)
i. uses
ii. advantages
iii. disadvantages
i. Rapid aneuploidy detection
Evaluation of unbalanced
translocations
ii. rapid results
iii. limited genomic coverage
array-CGH (microarray comparatice genomic hybridisation)
i. uses
ii. advantages
iii. disdvantages
i. Rapid aneuploidy detection
Detection of microdeletions
Detection of microduplications
ii. rapid results
info re: gene dosage throughout genome
iii. New assay, so unclear whether
abnormal results are pathogenic
variants or polymorphisms
lifetime risk of ovarian cancer in general population
1 in 70
genes associated with breast ca development (6)
BRCA1 &BRCA2
MMR genes” MSH2, MLH1, MSH6, PMS2
BRCA 1
i. lifetime risk of breast Ca
ii. lifetime risk of ovarian ca
i. 60-90% breast ca
ii. 40-60% ovarian ca
BRCA 2
i. lifetime risk of breast ca
ii. lifetime risk of ovarian ca
i. 45-80%
ii. 10-30% ovarian Ca
what’s the overall contribution of BRCA 1 and BRCA2 to breast ca (%)?
<2%
what is the risk of ovarian ca in women with BRCA 1&2 who opt for prophylactic BSO?
what happens to the risk of breast ca?
1% (peritoneal)
halved
which malignancies are MMR gene alterations most commonly associated with?
colorectal
endometrial
gastric
ovarian
risk of endometrial cancer with MMR defects?
50%
HNPCC risk of of:
i. ovarian cancer?
ii. endometrial cancer?
i. 4%
ii. 50%
how are tumours tested for HNPCC?
immunohistochemistry
syndromes associated with ovarian ca (3)
i. HNPCC = the artist formerly known as Lynch syndrome (MMR repair mutation)
ii. Peutz- Jegher syndrome
iii. Cowden disease
Peutz- Jegher syndrome
i. what is the mutation?
ii. clinical features?
iii. what is the lifetime risk of GI malignancy
?
iv. what is the lifetime risk of endometrial cancer
i. mutations
within the gene encoding serine/threonine protein
kinase 11 (LKB1)
ii.pigmented macules
of the mucous membranes and skin, gastrointestinal
polyps
iii. 30%
iv. 40%
aneuploidy risk evaluation
what 3 tests are done in 1st trimester?
nuchal translucency
nasal bone measurement
assessment of blood flow in ductus venosus
in trisomy 21 what would you expect to happen to:
- nuchal translucency
- nasal bone measurement
- blood flow in ductus venosus
- increased
- absent/ hypoplastic nasal bone
- absent/ reversed a wave
combined testing
1. which trimester is combined test done?
- what are the 3 parts?
- what would happen to result in down syndrome?
- 2nd trimester
- NT, bHCG, PAPP-A
- ^^ NT, ^^bHCG, vv PAPP-A
- which semester is triple/ quadruple screen done in?
- what tests are in the triple screen?
- what tests are in the quadruple screen?
result for these if Down syndrome
- α-FP + ^^ β-hCG + vv unconjugated oestradiol
- as above + ^^inhibin
