Cyto Flashcards
Down syndrome
1/700 liveborn
~75% spontaneously abort
- phenotypic features: dysmorphic, ID, hypotonia, congenital heart disease, GI anomalies, leukaemia
Life expectancy 60 years except for severe cardiac anomalies (40%)
-5% have severe GI anomalies (mostly duodenal stenosis)
-15-20 fold increased risk of leukaemia (1%)
- most adults will develop Alzheimer’s disease, all >35 years old develop it
-95% are due to free T 21, 3-4% result from Robertsonian translocation, 1-2% result from mosaicism
- recurrence risk related to mat age. 1/100 at 40 nondisjunction risk
Trisomy 18
Phenotype: small/IUGR, hypotonic or hyper, hand posturing with overlapping finger, small face and chin, rocker bottom feet, severe ID, malformations seen in 95% of patients (cardiac defects, GI and renal)
Frequency 1/5000-8000, 4F:1M
Overall survival:30% die within 1st month, 50% die within 2 months, 90% die within 1 year
95% result in spont abort.
Trisomy 13
Phenotype:
Freq:1/10 000-15,000
Same survival rates as T18
>95% spontaneously abort
>20% due to a robertsonian translocation
Lyon hypothesis exceptions
- inactivation not always random (with structurally abnormal X non random inactivation seen)
- inactivation not complete : a number of genes escape, may be up to 15% of all x-linked genes escape inactivation in some way
- inactivation reversible in development of germ cells
- explains manifestations of x linked disorders
- explains variability of clinical manifestation in females
- explains difficulty in biochemical carrier detection in female carriers
X inactivation mechanisms
Altered chromatin structure
Differentials methylated DNA
CpG islands in silenced genes methylated
X inactivation centre at Xq13.2 (Cis for Inactived)
XIST gene: x inactive specific transcript, uniquely expressed from the inactive but not the active X
Turner syndrome
Common cause of short stature and primary amenorrhea
Incidence -1/1500-5000 liveborn females, 1/30-50 (3%) of female conceptuses, 1/100 survive to delivery
-2/3 retain mat X, recurrence risk low
-50% 45,X; others -structural x abnormalities
-other phenotypes: short stature, deems, broad chest with hypoplastic nipples, webbed neck, gonadal dysgenesis, cardiac anomalies, renal anomalies
Klinefelter syndrome, 47 XXY
1/500 male newborns, no recurrence risk
1/2 pat meiosis 1 errors ( no age affect noted) - remainder may M 1 or 2 errors (age effect seen with M 1 errors only)
-48, XXYY similar but with more ID
Phenotype: small testes, abnormal facies, sparse facial hair, gynecomastia, scoliosis, low muscle tone, enter puberty normally but testicular insufficiency develops soon after, phallus usually normal or micro, untreated hypoandrogenizayion leads to eunuchoid habitus, occasional minor ID
Specific defects include: verbal memory, fluency, speed of verbal processing, overall language skills
Reading disabilities are common
Infertility very common, fibrosis of semiferous tubules, exogenous testosterone does not help, normal offspring in few cases of successful reproduction
Robertsonian translocations
Fusion of two Acrocentric chromosomes, whole arm exchanges (13, 14, 15, 21, 22), short arms are lost
-90% are dicentric (2 centromeres), carriers are balanced
Common recurring chromosomal rearrangement 1/1000 individuals
-rob(13q14q) and rob(14q21q) are most common
Often associated with trisomy of chromosomes involved, increased risk for uniparental disomy
Risk to have a child with unbalanced segregants
-theoretical risk of abnormal live birth 33%
Rob(14;21)(q10q10) female carrier-10-15% risk, male carrier 2% risk
Rob(13;14)(q10q10) female carrier 1%, male carrier <1% probably
Reciprocal translocation
Interchange of genetic material between non homologous chromosomes
Balanced translocations 1/500 individuals
Carriers are at risk for multiple miscarriages and abnormal offspring
Translocations do not disjoin as normal during neurotic segregation, they form a quadrivalent in pachytene stage of meiosis
Types of segregation: alternate, adjacent 1 (segregation of non homologous centromeres), adjacent 2 (segregation involving homologous centromeres), 3:1 disjunction
-prenatal diagnosis 6-9/10 000, if de novo 6-8% risk of phenotypic abnormality (empiric)
Paracentric inversions
Do not involve centromere
Often results in acentric fragments and dicentric chromosomes
Pericentric
Involves centromere along with inversion of material from long and short arm
Can result in recombinant chromosomes and unbalanced offspring
Outcomes of segregation of translocations
Alternate or adjacent 1: most frequent, can have normal/ balanced or unbalanced segregants, dependent of chiasma placement
Adjacent 2 or 3:1 segregation: will always lead to unbalanced segregants
Unbalanced segregants: both monosomic and trisomic segments present, makes phenotype/karyotype correlations difficult, counselling difficult but imperative that
Outcomes of reciprocal translocations
Unbalanced risks
~11-12% risk of unbalanced segregant
-empiric data from prenatal diagnosis studies : ascertainment dependent, previous child with unbalanced translocation (~20% risk), previous multiple sabs (~3-4%), other ascertainment (~7% risk)
Balanced translocations
Incidence of ID
-increased in de novo rearrangements
->20% of translocations in newborns de novo. 55% of translocations with ID de novo
3/1000 individuals with ID with de novo translocations
Incidence of congenital anomalies - increased in de novo rearrangements
Williams syndrome
Del(7)(q11.23) Cardiac defects 75%- supravalular aortic stenosis, elastin gene deletions Loquacious personality, outgoing Infantile hypercalcemia Dysmorphic facies: elfin features
Digeorge 22q deletions
Dysmorphic features, cardiac defects (VSDs, conotruncal), Cleft palate, velopharyngeal incompetence (hypernasal speech), learning disabilities (99%) , thymus hypoplasia/aplasia (t cell dificiency), hypoparathyroidism (hypocalcemia) , ID
-one of most common 1/2000
Can be inherited (~10%)
Miller Dieker syndrome
Type 1 lissencephaly (can be isolated)
Dysmorphic facies
Smith Magenis syndrome
Dysmorphic facies (brachycephaly, flat mid face, prognathism)
Behavioural abnormalities (self destructive in 75%)
Peripheral neuropathy
Sleep disorders
ID
Deletion 17p11.2
Prader Willi syndrome
Moderate ID Neonatal hypotonia Hypogenitalism Hyperphagia -obesity Short stature Small hands and feet Characteristic facies Del(15)(q11q13) Paternal deficiency
Angelman syndrome
Severe ID Seizures Absent speech Paroxysms of laughter Tongue protrusion Stiff, ataxic gait Characteristic facies Maternal deficiency 15q11-q13 or UBE3A mutation
1p36 deletion syndrome
Variable break points
Accounts for ~0.5-1.2% of idiopathic ID
Prevalence ~1/5 000
Can be terminal or interstitial
22q13 syndrome
McDermid-Phelan
Hypotonia Severe language delay Mild facial dysmorphism ID Deletion of SHANK3
Beckwith-Wiedemann syndrome
Macrosomia, macroglossia Omphalocele Hypoglycaemia Transverse earlobe crease Hemihypertrophy Advanced bone age Increased risk of malignancy Duplication of 11p15(Pat) (paternal disomy)
Chorionic villus sample
9-12 weeks
Aspiration of sample of growing placenta
Advantages: earlier in gestation
Disadvantages: not testing fetus directly, can’t test for NTDs, generally planned pregnancies since early sampling
Amniocentesis
After 14 weeks
30 ccs of fluid at 16 weeks
Fluid contains skin and gut cells from baby
Advantages: testing fetus directly, can test for NTDs (increased AFP)
Disadvantages: later in pregnancy
Limitations of chromosomal analysis
Can’t determine size generally, limited resolution
Balanced vs unbalanced rearrangements
Origin of derivative chromosomes
Marker chromosomes
Limitations of FISH
Must know region to test Only get result for that region Expensive if multiple tests Time consuming Each region analyzed separately
Components of genome
3 billion base pairs About 0.8% codes for proteins About 40-50% of DNA repetitive 20-25000 genes Gene density: 1/45 kb Gene size: average 20 kb, enormous variation
Microarray indications
First line test for:
1) multiple anomalies not specific to a well-delineated genetic syndrome
2) apparently non-syndromic DD/ID
3) ASDs
Prenatal: u/s abnormalities, >3 fetal losses, POCs
Can be utilized if no cell growth when chromosomes are ordered
Oncology: generally used in Leukemia and lymphomas to direct treatment
Microarray
Runs of homozygosity
Smaller stretches of homozygosity (<3 Mb) are common in the outbred population
When observed on a single chromosome- could be UPD
When distributed throughout genome - usually represents segments of autozygosity or regions that are identical by descent (IBD), can indicate consanguinity
