Chromosomal Abnormalities Flashcards
What is the normal male karyotype?
46XY
What stain is used for G-banding?
Giemsa stain
What is a telomere and what is its function?
- DNA + protein cap
- Ensures DNA replication to tip
- Tether to nuclear membrane
What are light bands?
- Less condensed chromatin
- Transcriptionally active
- Gene + GC rich
What is the function of centromeres?
- Joins sister chromatids
- Essential for chromosome segregation at cell division
What are dark (G) bands?
- Condensed chromatin
- Gene poor, AT rich
What is Cytogenetic testing?
G banded routine karyotype
Karyotype = test of whole genome but normal result does not exclude genetic problem
What gene is CF, Huntington’s and SCA on?
CF = gene 7 Huntington's = gene 4 SCA = gene 11
What is the limit of detection of Karyotype resolution?
Able to see changes (e.g. deletion or extra piece) down to 5 million bases = limit, won’t see any smaller
What is DNA sequencing used for?
To look at DNA one base at a time
Name some cytogenetic techniques
Karyotype, FISH, Array-CGH
Name some molecular genetic techniques
MLPA, DNA sequencing
What is a Karyotype and what is the standard notation?
Karyotype = representation of person’s chromosome complement
Standard notation:
- total no. chromosomes
- followed by sex chromosome composition
- followed by any abnormalities detected
- changes in whole chromosome number (= chromosomal aneuploidy) = denoted using + or - sign against particular chromosome
Are trisomies viable?
No, common at conception only, never born
What is the only chromosomal monogamy survivable to term?
Turner syndrome (monosomy X)
What is a common mechanism of chromosomal aneuploidy?
Non-disjunction at meiosis (can occur in meiosis I or II)
What is Down syndrome?
Trisomy 21 - most common autosomal trisomy
How is Down syndrome detected?
- Structural abnormalities in antenatal scans, screening tests, or facial appearance at birth
- Increased nuchal translucency measurement @ 12 weeks
What is the presentation of Down syndrome in infants?
- muscle hypotonia
- large tongue
- umbilical hernia
- brush field spots
- single player crease
- congenital defects
What is the presentation of Down syndrome in adults?
- Developmental delay, intellectual disability
- Distinctive features - up slanting palpebral fissures, low-set ears, epicanthic folds, flattened nose, single transverse palmer crease, bilateral 5th finger clinodactyly, sandal gap deformity
- Short stature, obesity
- Increased risk congenital HD, thyroid disorders, conductive hearing loss, antlantoaxial instability, immune dysfunction, leukaemia, seizures, psychiatric illness, dementia
What is mosaicism?
Some of cells have genetic abnormality but also have proportion of cells without genetic abnormality.
Proportion can be high or low, can be throughout body or confined to particular section.
What is the effect of mosaicism?
- milder features (if mosaic with normal karyotype)
- can allow severe chromosomal abnormalities to be viable e.g. mosaic trisomy 8 and 22
- caused by post-zygotic errors in mitosis (nondisjunction or trisomy rescue)
What is germline mosaicism?
Mutated cells only present in person’s testis or ovaries.
Person may be completely asymptomatic but at risk of having multiple affected children.
What is Edward’s syndrome?
- Trisomy 18
- 2nd most common autosomal trisomy
- Majority miscarried or stillborn, some survive to 1 year
- IUGR
- Severe developmental delay
- Seizures
- Structural abnormalities - heart, eye, craniofacial, cleft lip/palate, urogenital, skeletal defects
- Arthrogryposis
- Clenches hands with index and 5th fingers overriding 3rd + 4th
- Rocker-bottom foot with prominent calcaneus
What is Patau syndrome?
- Trisomy 13
- High rates of miscarriage/still birth
- Severe developmental delay
- Microcephaly
- Seizures
- Holoproscencephaly (failure of forebrain to divide properly)
- Neural tube defects
- Structural defects - craniofacial, eye, skeletal, omphalocele, cleft palate, urogenital, heart, cutis aplasia
Give examples of triploidy
69, XXX
69, XXY
69, XYY
What are the 2 types of triploidy?
- Diandry
- egg fertilised by 2 sperm (dispermy)
- egg fertilised by diploid sperm
- large placenta, small fetus
- risk of partial molar pregnancies + choriocarcinoma - Digyny
- diploid egg fertilised by single sperm
- small placenta, small fetus
What features are seen in Triploidy’s?
- Miscarriage/stillbirth or early neonatal death (unless mosaic)
- Prematurity
- IUGR
- Craniofacial dysmorphism
- Hypotonia
- Eye/gut/brain/cardiac/limb/genito-urinary abnormalities
Why is sex chromosome aneuploidy milder than autosomal aneuploidy?
- Y chromosome is small
- One X chromosome inactivated in female cells = natural mechanism for suppressing gene expression from extra X chromosomes
What is a Barr body?
Condensed X chromosome - not totally inactive
What is Turner syndrome?
- 45,X
- Short stature, neck webbing, broad chest with widely spaced nipples, lymphedema of hands + feet, low-set ears, increased carrying angle at elbow
- Lack of sexual development at puberty, streak ovaries, primary amenorrhoea, infertility
- Normal intelligence
- Heart defects (esp. coarctation + bicuspid aortic valve), kidney abnormalities
- Increased risk IBD, hypothyroidism
What are the treatment options for Turner syndrome?
- Hormone therapy (GH in childhood, oestrogen in adolescence)
- Surgery for webbing
- IVF/egg donation
What is Klinefelter syndrome?
- 47,XXY
- Primary hypogonadism (increased FSH/LH, decreased testosterone)
- Pubertal gynaecomastia
- Small testes
- Delayed/incomplete development of secondary sexual characteristics
- Relatively tall stature
- Infertility
- Variable impact on development/learning
- Increased risk health problems which affect females
- Reduced risk X-linked disease
What are the treatment options for Klinefelter syndrome?
- Testosterone
- Surgery for gynaecomastia
- Fertility treatment
What is XYY syndrome?
- 47, XYY
- Tall stature
- Usual normal intelligence
- Mild developmental delays
- Severe acne?
- Aggression or antisocial behaviour?
- Most XYY men unaware
- Normal testosterone levels
- Normal fertillity
What is a balanced reciprocal translocation?
- Usually asymptomatic (unless deletion or gene disrupted at breakpoint)
- Risk of infertility/recurrent miscarriage
- Variable risk of liveborn offspring with unbalanced arrangement
What are acrocentric chromosomes?
- have v small p arm
- can form Robertsonian translocations
What are Robertsonian translocations?
- Can form between homologous or non-homologous acrocentric chromosomes
- Most common between 13+14
- Also common between 14+21
What are the features seen in Robertsonian translocations between 13+14?
- Carriers phenotypically normal
- Risk of miscarriage normal but some carriers present with infertility or recurrent spontaneous abortions
- Translocation trisomy 14 - frist trimester loss
- Translocation trisomy 13 (Patau syndrome)
Name the 3 different patterns of chromosomes that can cause Down syndrome
95% have 3 separate copies of chromosome 21
3-4% have extra copy of chromosome 21 due to Robertsonian translocation
1-2% have mosaicism with normal + trisomy 21 cells from:
1. Post-zygotic mitotic non-disjunction
2. Post-zygotic loss of chromosome 21 from trisomic zygote = trisomy rescue
What is 22q11.2 deletion syndrome?
- aka DiGeorge Syndrome = Interstitial deletion - heart anomalies - characteristic facies - palatal abnormalities - thyme hypoplasia - immune deficiencies - hypocalcaemia - short stature - long thin fingers - conductive deafness - learning disabilities - psychiatric illness - renal anomalies
What is Fluorescent in situ hybridization (FISH)? Describe it.
Detects micro deletions
- Construct DNA probe + fluorescently label it
- Probe applied to chromosome + incubated while hybridising - several wash steps
If probe bound twice in expected place = normal result
What is Array CGH? Describe it.
Allows systemic testing of thousands/millions of genomic regions at one time
- Inert base
- Copies of 1 DNA probe fixed to spot
- Add more spots - each spot contains different DNA probe corresponding to specific region of genome
- Reference genomic DNA + Patient’s fragmented + fluorescently labeled
- Equal amounts of reference DNA + test DNA hybridized to array
- Measure ratio of reference DNA to test DNA bound to each probe spot
How good is the diagnostic performance of Array-CGH?
Has replaced karyotype for most postnatal (+ now prenatal) cytogenetic testing as its rarely misses abnormalities that are often missed by routine karyotype (balances rearrangements, inversions, triploidy)
How detrimental are duplications?
Features milder than equivalent deletion
How detrimental are inversions?
- Usually asymptomatic
- May damage genes at or near breakpoints
What is ring chromosome 20 associated with?
Seizures
What is ring chromosome X often mosaic with?
Turner syndrome [45,X/46,X,r(X)]
