Blood Module Flashcards
(43 cards)
1
Q
What causes (straight forward) Down Syndrome?
A
- WHO figures = 1 in 1000 worldwide births
- 95% due to non-disjunctional trisomy 21:
90% of which are the result of maternal meiotic errors, 3/4 being meiosis I and 1/4 meiosis II (of which some will be ‘set-up’ by meiosis I errors) - 10% due to paternal meiosis error
- non-disjunctional +21 has low risk of recurrence, less than 1% if <30 years and is couple 1st +21 pregnancy
- although cannot exclude possibility of gonadal mosaicism
(small number of gonadal cells have extra 21 and can therefore produce either normal or +21 gametes) - DS critical region is 21q22.13q22.2 but phenotype of DS overlaps many regions of 21 (see pheno map in GandS)
2
Q
Discuss other ways Down Syndrome can exist.
A
- Mosaic DS, a proportion of cells have an extra 21
- Presence of normal cells will ameliorate the phenotype but this depends on the cell lines affected
- occurrence is usually postzygotic:
could be a 47,+21 conceptus followed by anaphase lag
could be a 46,N conceptus followed by malsegregation (the 45,-21 would be lost due to being disadvantaged)
(the extent of the mosaicism is determined by when this event occurs) - QF-PCR could be used to work out how the mosaicism came about, 3 different alleles present would be an indication of an originally trisomic conceptus
- isochromosome 21 DS
- Robertsonian DS: de novo in 3/4 or familial in 1/4 (usually from the mother)
- 14:21 rob is most common
- risk of DS offspring if rob carrier is 15% for mother but <1% for father due to disruption of spermatogenesis
- translocation DS: very rare (2:2 or 3:1 segregation could give rise to partial trisomy for chr21 and could include DS critical region 21q22.2q22.3).
3
Q
Clinical features of Trisomy 21
A
- 50% have a heart defect (atrioventricular septal defect)
- hypotonia (floppy baby)
- characteristic facial features: upslanting palpebral fissures, epicanthic folds, small/dystrophic ears that are low set, flat nasal bridge, small nose.
- single palmar crease
- wide gap toes (sandal gap)
- brushfield spots (iris spots)
- duodenal atresia (1st part of bowel not developed properly)
- open mouth and high palate
- grow at different rates to general pop (Clin Gen have growth charts)
- global developmental delay
- respiratory infections
- increased risk of leukaemia: particularly AML, transient abnormal myelopoiesis. Increase in myeloid blasts to a level that would be diagnostic for AML- can spontaneously resolve but some become Acute Megakaryoblastic Leuk. GATA1 mutations!
- increased risk of Alzheimer’s
4
Q
Discuss features of Edward Syndrome
A
- trisomy 18
- less common than +21
- around 1 in 6000 births
- usually maternal non-disjunction
- could be mosaicism or malsegregation of translocation involving chr18
- survival of just a few days
- only 10% live up to a year and this is likely due to mosaicism
- they grow slowly (IUGR) and have a low birth weight
- profound developmental delay
- central nervous system malformation
- heart defects
- ROCKER BOTTOM FEET
- characteristic ‘CLENCHED HAND’ with overlapping fifth and index fingers
- micrognathia
- prominent occiput
- low set ears
- short sternum
- exomphalos (organs in a sac outside abdomen due to weakness of membranes)
5
Q
Discuss features of Patau Syndrome
A
- around 1 in 12000 births
- Trisomy 13
- 95% spontaneously abort (tissues)
- maternal age risk
- usually non-disjunction
- could be gonadal mosaicism, translocation involving 13 or rob(13;14)
- only survive for a few days and only 10% go on to live for a year (this is likely due to mosaicism)
- they have MIDLINE defects
- holoprosencephaly (forebrain fails to divide into two hemispheres)
- small or poorly developed eyes which are close together (hypertelorism)
- cleft lip and palate
- spinal cord abnormalities
- heart defects: holes in the middle of the heart
- extra fingers and toes
- prominent heels
6
Q
What causes DiGeorge Syndrome?
Can it be inherited?
A
22q11.2 deletion - mediated by low copy repeats.
Size of deletion depends on which LCR’s are involved. Minimum size ~1.5Mb - maximum size ~3Mb.
Typical size is 3Mb.
Most often de novo but can be inherited from normal parent.
7
Q
What gene contributes most to DiGeorge phenotype?
A
TBX1
8
Q
How common is DiGeorge? Is there a reciprocal duplication?
A
- most common deletion at 1 in 4000 births,
- reciprocal duplication not as common ?due to milder phenotype.
9
Q
Describe some clinical features of DiGeorge Syndrome.
A
VARIABLE phenotype.
- 75% have heart defects and this is usual reason for referral:
Outflow tract abnormalities: tetralogy of fallot (group of 4 abs that occur together), VSD, interrupted aortic arch, ASD, truncus arteriosus, TGA.
Other features include:
- subtle characteristic facial appearance
- cleft palate
- failure to thrive
- neonatal seizures
- immune problems (recurrent infections)
- low calcium
- kidney problems
- learning problems
- speech and feeding problems
- long, thin fingers.
10
Q
What is the origin of the pattern of abnormalities seen in DiGeorge?
A
Abnormal neural crest development - these cells are involved in formation of many of the structures affected e.g. skull bones, palate, face, outflow tract of heart and thymus.
-3rd and 4th pharyngeal pouch fails to develop normally during twelfth week of pregnancy.
11
Q
How do we treat a sample which arrives as suspected DiGeorge?
A
Neonate or awaiting surgery? - urgent FISH and report within 3 calendar days.
Others - routine. FISH cultures or if other queries then would just do microarray.
12
Q
Why are DiGeorge patients awaiting surgery urgent?
A
Result needed prior to any surgery on a ?DG patient as they may need irradiated blood.
If normal blood is used an infant may develop graft v host disease due to immune deficiency.
Irradiated blood is very expensive and therefore don’t want to use unless it is confirmed to be needed e.g. confirmed DiGeorge diagnosis.
13
Q
What are the features of UPD14?
A
Paternal UPD:
- more severe
- growth retardation (pre and post)
- major neurological compromise
- obstetric complications
- poor survival
- bell shaped thorax (can be seen on detailed scan).
Maternal UPD14 (Temple syndrome)
- less severe
- growth retardation (pre and post)
- intellectual development low normal to normal.
14
Q
What is the critical segment involved in UPD14?
A
- 14q32.2
15
Q
A normal parent carries a rob(13;14) or a rob(14;21) which the offspring inherits but despite the balanced karyotype, the child has a phenotype. What might be an explanation?
A
UPD14 caused by trisomy rescue and ‘kicking out’ of the other parents chromosome.
16
Q
If a phenotypic baby has a rob(14;14) but is otherwise balanced, what could a cause be?
A
The rob(14;14) could represent an initially 45,-14 conception with subsequent duplication of the 14 into a i(14q)and thus UPD14.
17
Q
What can UPD11 cause?
Which region is of particular importance?
A
Beckwith-Wiedemann Syndrome and Silver-Russell Syndrome which are countertype syndromes.
Important region implicated in both is 11p15.
18
Q
Which type of UPD causes BWS?
A
Paternal UPD, specifically mosaic segmental UPD of 11p15 caused by mitotic somatic rearrangement.
This causes 20% of BWS.
(FYI the countertype UPD(11)mat is assumed lethal and the cells die.)
19
Q
What are the genes/regions involved in BWS due to UPD11 called?
A
2 regions are expressed according to the parent of origin:
- Differential methylated region 1 (DMR1) controls IGF2 which is paternally expressed and H19 which is maternally expressed,
- DMR2 controls KCNQ10T1 (pat) and CDKN1C (mat).
= over expression of IGF2 and KCNQ10T1 (both paternal)
= H19 and CDKN1C are silenced as there’s no maternal allele.
20
Q
What are other less common causes of BWS?
A
- duplication of paternal 11p15 region
- epigenetic error (aberrant methylation of maternal region)
- deletion of maternal 11p15.
21
Q
What is the countertype of BWS? What is the main cause?
A
- Silver-Russell Syndrome
- Aberrant methylation of 11p15 in up to 50% of cases
- Specifically epigenetic error at DMR1
- H19 (mat) is bi-allelically expressed whereas IGF2 (pat) is underexpressed.
- can also be caused by structural aberrations of 11p.
22
Q
What are the clinical features of SRS?
A
Features are the opposite to that seen in BWS:
- slow growth (pre and post birth),
- low birth weight
- FTT.
- head growth is often normal so they appear to have a large head.
22
Q
What else can SRS be caused by?
A
UPD7mat in around 10% of cases.
23
Q
Cri du Chat Syndrome
- what region does it involve?
- what mechanism is behind its occurrence?
- what are the clinical features?
A
- A deletion of 5p, specifically the regions 5p15.2 and 5p15.3,
- Deletions can be terminal, interstitial or caused by a balanced translocation in a parent,
- could be caused by a ring,
- deletions vary in size and this correlates with phenotypic severity,
- the 5p region contains a lot of repetitive sequence which may cause its instability. Many individuals have similar breakpoint, however there is NO COMMON RECURRING breakpoint.
- mostly paternal origin and likely occurs during gamete formation.
Clinical features:
- high pitched ‘cat like’ cry (hence the name)
- facial dysmorphism,
- mental retardation,
- microcephaly.
23
Wolf-Hirschhorn Syndrome
What causes it?
What specific rearrangement can lead to WH phenotype?
What are the clinical features?
It is a deletion of 4p.
- Deletions are often cytogenetically visible, but may need array,
- the 4p region is unstable due to high amount of repetitive sequence,
- Critical region is at 4p16.3 and contains WHSCR
- the size of the deletion correlates with the phenotypic severity,
- can be terminal, interstitial or caused by a balanced rearrangement in a parent,
- could also be due to a ring chromosome,
- could be caused by the t(4;8) in a parent (2nd most common recurrent trans).
Clinical features:
- Greek warrior helmet facial appearance: widely spaced protruding eyes; broad, flat nasal bridge and high forehead.
- delayed growth and development,
- FTT and feeding problems,
- weak muscle tone,
- mild to severe I.D,
- good socialisation skills in comparison to their I.D,
- seizures in 90-100%.
24
17p11.2
What is this region associated with?
What causes these syndromes?
What are the clinical features of each?
17p11. 2 deletion is Smith-Magenis Syndrome (SMS)
17p11. 2 reciprocal duplication is Potocki-Lupski Syndrome (PTLS)
A series of repeat elements at 17p11.2 cause non-allelic homologous recombination and produce reciprocal deletion-duplication events. 17p is one of the most recombination prone regions in the genome.
The most common deleted/duplicated region is ~3.7Mb in size and is between the distal and proximal repeat. 90% of the deletions are the classic size.
Other repeats produce other deletion sizes but are rarer (~1.5Mb to 9Mb).
A key gene affected is RAI1.
Clinical features of Smith-Magenis Syndrome:
- distinctive dysmorpholgy,
- mental defect (mild-moderate)
- fractious behaviour
- sleep disturbance is characteristic. Sleepy in the day and struggle to sleep with frequent awakenings. Reversal of circadian pattern of melatonin secretion.
- self injury and self mutilation. Diminished pain sensitivity.
Clinical features of Potocki-Lupski Syndrome:
- features are milder
- normal facies
- mild MR/borderline normal cognitive function.
- ADHD common
- autistic features
- most have short stature.
26
What are the clinical features of UPD11?
Key clinical feature is overgrowth of tissues and organs. Tissues with greater fraction of UPD11p15 show greater degree of overgrowth and give classic hemi-hyperplasia (big clinical indicator).
27
16p11.2p12.2
How many LCRs does this region have?
What's the most common change we see at this region?
What are the clinical features of each?
This region harbours 5 'breakpoints' which are involved in various deletion/duplications.
- the 16p11.2 microdeletion between BP4-BP5 of ~600kb is one of the most frequent single locus causes of neurodevelopmental disorders and ASD.
- clinical manifestations vary due to incomplete penetrance and variable expressivity but include the following:
Developmental delay and language delay
Mild I.D
Social impairment
Seizures
Variable dysmorphism
Predisposition to obesity
- the reciprocal duplication of above is also ~600kb and again has very variable features and asymptomatic carriers. Common features include:
Developmental delay, speech and language delay, learning difficulties etc
Opposite to those with the deletion they can be thin and struggle to gain weight.
BP2-BP3 of 16p11.2 harbours a distinct ~200kb microdeletion which includes the gene SH2B1. This gene has been reported in association with developmental delay and severe early onset obesity.
There are many other dels/dups which involve this region including large rearrangements of up to 8Mb.
28
1q21. 1 region:
- what types of changes do we see here?
- what size are the changes and what are the clinical features which are associated with each?
The 1q21.1 region contains extensive low copy repeats making it susceptible to rearrangement. There are 2 distinct regions:
- the TAR region
- the distal 1q21.1 region.
There is a region at 1q21.1 of ~1.3Mb which can harbour a deletion or its reciprocal duplication. This occurs between BP3-BP4 and is referred to by 'Unique' as a Class-I del/dup.
Class-I deletion at 1q21.1:
Highly variable phenotype, mild to severe developmental delay, dysmorphic features, microcephaly.
Asymptomatic and mildly affected parents have been noted.
(Variable expressivity and reduced penetrance)
Class-I microduplications at 1q21.1:
Enriched in neurodevelopmental disorders Vs controls......? Predisposes to neuro and autism?
Deletion occurs more commonly, dup may just be a susceptibility locus.
Patients display features such as macrocephaly (opposite to deletion!), developmental delay and dysmorphic features.
1q21.1 region and TAR:
Thrombocytopenia - Absent Radius.
BP2-BP3 encase the TAR region - the minimal region is ~200kb.
Characterised by reduction in number of platelets and by absence of the radius (in this Syndrome the thumb is preserved). In other similar syndromes the thumb is missing such as Fanconi .
Class-II dels and dups:
When the deletion or duplication is larger and encompasses both the distal BP3-BP4 region as described above and the BP2-BP3 TAR region it tends to be larger at ~2Mb. Unique refer to these as Class-II dels/dups.
The Class-II deletion has a much broader phenotype.
29
How does the fetal spot test work?
Fetal haemoglobin is resistant to alkali denaturation, whereas adult haemoglobin is susceptible.
Exposing the blood spot to sodium hydroxide will turn an adult blood sample a yellow/brown whereas a fetal blood sample will stay red/pink.
31
What region is implicated in Prader-Willi and Angelman Syndrome?
15q11-q13
32
What determines whether the phenotype is PWS or AS? What mechanism is responsible?
It is determined by the parent of origin.
| Genomic imprinting.
33
What is the most common cause of Prader-Willi Syndrome?
75% is caused by a deletion of paternal chr 15 including SNRPN.
34
What is the basic cause of Prader-Willi or Angelmans?
| How does this happen?
Loss of activity of a segment of chr15.
| This occurs either by a physical loss of the region e.g. a deletion or by uniparental disomy.
35
What are the remaining causes of PWS?
25% caused by maternal UPD
| 1% result of imprinting centre issue e.g. a functional defect or microdeletion of the imprinting centre
36
What is the most common cause of Angelmans?
70% caused by a deletion of maternal chr 15q11-q13 (UBE3A gene).
37
What are the remaining causes of AS?
10-15% UBE3A mutation (UBE3A shows biparental expression except in the brain where only the maternal copy is expressed)
2-4% imprinting centre issue such as point mutation or deletion of imprinting centre
1-5% paternal UPD of chr15 (much rarer as paternal meiotic errors are rarer)
38
Why is the deletion seen in PWS/AS recurrent? How big is it?
- Low copy repeats present in the 15q11-q13 region mediate deletions by non-homologous recombination.
- Deletion can be larger class 1 (5.9Mb) or smaller class 2 (5Mb) dependant on the breakpoint.
- BP1 and BP3 produce class 1 deletions.
- BP2 and BP3 produce class 2 deletions.
- Behavioural phenotype is slightly worse with class 1.
- Larger deletions can be seen and exhibit are more severe phenotype.
39
What controls the genes that are implicated in PWS and AS?
The imprinting centre. It controls expression of genes in this region, switching them on or off depending on parent of origin.
(Imprinting is reset at each generation to reflect the sex of the donor parent.)
40
Name some of the typical phenotypic features seen in PWS.
- Infantile hypotonia
- insatiable appetite and hyperphagia (over eating)
- overweight/obesity
- mild to moderate mental retardation
- behavioural difficulties e.g. Temper tantrums, stubbornness
- skin picking
- facial dysmorphism
- hypogonadism
- sleep abnormalities.
41
Name some of the typical features seen in AS.
- AS primarily affects the nervous system
- Severe mental retardation
- Seizures
- Sleep difficulties
- Difficulty with balance and walking
- Characteristic behaviour and movements e.g. laughing, smiling, hand flapping
- Happy demeanour and excitable.
42
What are the recurrence risks associated with PWS/AS?
- deletion/UPD
- imprinting centre defect
- unknown
Low for UPD and typical de novo deletions,
50% for an imprinting centre defect
50% for an UBE3A mutation
Unknown? Up to 50%
43
What is a susceptibility loci?
Risk factor!
Often associated with developmental delay, ID, autism, epilepsy, psychiatric disorders etc. but are associated with being reduced penetrance and variable expression and seen in normal individuals.
