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Chromosome Disorders Flashcards

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1
Q 
What mediates the deletions/duplications on 1q21?
Fully describe the class 2 deletions of this region.
A

4 large blocks of LCRs mediate rearrangements via NAHR

Class 2: large 1.35-2Mb deletion, includes TAR region and distal q21.1 region - approx 25 genes

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2
Q

What are the clinical features of 1p36 deletion syndrome?

A 
Developmental delay
Slow closing fontanelle
Hypotonia
Delayed/absent speech
Growth retardation
Eye defects
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3
Q

What is the critical locus for WHS? Name 3 clinical features.

A 
4p16.3
Typical facial appearance
Growth delay
Seizure
Mental retardation
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4
Q

Describe TAR

A

Incomplete penetrance, absent radius with thumbs present, thrombocytopenia
RBM8A gene - ? second hit model, compound inheritance model

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5
Q

Where is NRXN1? Describe deletion syndrome

A

2p16.3
Moderate/severe ID, psychiatric disorders, severe language delay
Reduced penetrance and variable expressivity

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6
Q

What is the locus and gene for Mowat-Wilson syndrome? Name 2 clinical features

A

2q22 - ZEB2
Hirshprung disease
Genitourinary anomalies
Characteristic facial features

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7
Q

Give me 3 facts about VHL

A

3p25
AD familial cancer syndrome
Renal cell carcinomas in approx 70%

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8
Q

Give 3 features of 3q29 microdeletion syndrome

A

Mild/moderate dev del
Microcephaly
Characteristic dysmorphic features
(Don’t forget about micdup! Milder than del, ocular and cardiac abns)

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9
Q

How can Wolf-Hirschhorn be inherited?

A

t(4;8) - Maternal

Other chrm rearrangements - Paternal

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10
Q

Critical region for Cri-du-chat syndrome and 3 clinical features

A 
5p15.3p15.2
High pitched cry
Microcephaly
Severe psychomotor and mental retardation
Cardiac abn's
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11
Q

Gene and region for Sotos and 3 clinical features

A

NSD1 on 5q35
Excessive physical growth 2-3yrs of age
Macrocephaly
Behavioural problems

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12
Q

Tell me 3 facts about Cornelia de Lange Syndrome

A

AD - Mutn of NIPBL/del’s 5p13.2
Delangin protein - controls interaction between cohesion complex and DNA of sister chromatids
Variable phenotype - mild to severe - slow growth, ID (severe to profound), self destructive behaviour

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13
Q

What is the clinical significance of UPD6?

A

Paternal UPD6 / patUPD 6q24

Neonatal benign transient diabetes - often resolved by 3yrs of age

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14
Q

Describe the clinical significance of UPD7

A

Maternal UPD - IUGR, retarded bone age, relative macrocephaly, characteristic facial features

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15
Q

What is the critical region for Williams Syndrome? Give 3 clinical features

A 
7q11.23 - ELN
Supravalvular aortic stenosis
Hypercalcaemia
Hypotonia
Devdel
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16
Q

Give 3 clinical features of mosaic trisomy 8

A

Skeletal abnormalities
Hypertelorism
Cardiac/renal abnormalities
Predisposition to haematological malignancy

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17
Q

What gives rise to abnormalities seen on 8p23.1?

A

OR gene clusters on 8p –>unequal crossing over

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18
Q

Give 3 CNVs at 8p23.1 and their clinical features

A

inv dup del (8p) - DUP thought to contribute most to pheno - devel, speech delay, hypotonia, microcephaly

8p23. 1 micdel - devdel, behavioural prob’s, CHD (GATA4)
8p23. 1 micdup - devdel, mild dysmorphism, cardiac defects

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19
Q

Describe Roberts Syndrome

A

Pseudothalidomide Synrome, rare AR, premature centrome separation and heterochromatin repulsion - ESCO2
Massive limb abnormalities, cleft lip and palate, microcephaly

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20
Q

Describe CHARGE syndrome

A

8q21 -CHD7

Coloboma, Heart defects, choanal Atresia, Retarded growth and development, Genital abnormalities and Ear anomalies

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21
Q

Describe WAGR

A

11p13 deletion syndrome
Wilms tumour, Aniridia, Genitourinary anomalies, mental Retardation
WT1 (Wilms Tumour supressor gene)
PAX6 (oculogenesis)

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22
Q

Describe the formation of the chromosome abnormality in Pallister-Killian Syndrome

A

Mosaic tetrasomy 12p/+iso(12p)

Non-disjuntion at Meiosis 2 followed by centromere misdivision and formation of the isochromosome

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23
Q

Give 3 clinical features of Noonan Syndrome

A

CHD (esp pulmonary valvular stenosis),
short stature,
webbed neck,
devdel

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24
Q

Give 3 clinical features of Patau Syndrome

A 
Trisomy 13
Congenital heart defects
Holoprosencephaly
Polydactyly
Cleft lip and palate
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25
Describe the 13q14 Deletion Syndrome
Retinoblastoma, Mild/moderate devdel Speech/language delay RB1 gene - tumour supressor gene, encodes pRB - controls cell cycle transition from G1 to S phase and normally stops other proteins from triggering DNA replication
26
Describe maternal UPD 14 - give the maternally expressed genes
Pre and postnatal growth retardation low to normal intellectual dev subtle dysmorphism GTL2, PEG11, RTL1
27
Describe paternal UPD 14 - give the paternally expressed genes
``` Polyhydramnios --> early labour Thoracic and abdominal wall defects Moderate/severe LD Subtle dysmorphism DLK1, DI03, RTL1 ```
28
Describe the 15q11.2 Deletion syndrome in as much details as you can
BP1-BP2 - approx 300-500kb - TUBGCP5, NIPA2, NIPA2 and CYFIP1 TUBGCP5 protein part of centrosome, rest are expressed in neuronal tissues VE and RP Increased suscep to neuropsychiatric/neurodevelopment problems and possibly seizures
29
Describe the 15q13.3 Deletion syndrome
BP4-BP5 (rarely BP3-BP5) CHRNA7 plays role in neurodevelopment - haploinsufficiency linked to phenotype incomplete penetrance
30
Give some key points to consider when assessing idic(15)
PWACR must be present to cause phenotype | Studies suggest parent of origin significant - MATERNAL clinically significant, PATERNAL ?benign?
31
Describe the 16p11.2 region
25 genes in region, inc MAP3, TBX6, SEZ6L2 and KCTD13 | Region flanked by 2x 147kb segmental dup with 99.5% sequence homology, these regions flanked by 2x 72kb seg dup - NAHR
32
Give 3 clinical features of 16p11.2 deletion syndrome
``` Speech/language delay Cognitive impairment Motor delay Seizures Behavioural prob's Congenital abn's Autism Macrocephaly ```
33
Give 3 clinical features of 16p11.2 duplication syndrome
Microcephaly Motor delay ADHD Seizures
34
Describe the 16p11.2-p12.2 Microdeletion syndrome
7.1-8.7Mb - flanked by segmental duplication - does not overlap 16p11.2 micdel/dup Common distal BP, variable proximal BP Minor facial anomalies, feeding difficulties, sig speech delay, ear infections OTOA - candidate gene for ear infections?
35
Give the gene, location and 3 clinical features of Rubinstein-Taybi syndrome
``` CREBBP - 16p13.3 Microcephaly MR CHD Increased risk tumour development ```
36
Give the key gene, location and 3 clinical features of Miller Dieker Syndrome
``` PAFAH1B1 - 17p13.3 (258kb critical region) Lissencephaly Microcephaly Seizures Severe MR Rarely survive beyond childhood ```
37
How many classes of 17p13.3 microduplication syndrome are there?
3 Class 1 - YWHAE not PAFAH1B1 - autism, behavioural prob's, dysmorphic, overgrowth Class 2 - YWHAE, PAHFA1B1 +/- CRK - Mild/mod devdel, hypotonia, dysmorphism Duplication of PAFAH1B1 alone - microcephaly, severe growth restriction
38
Describe Smith-Magenis Syndrome
17p11.2 Microdeletion Mild/moderate MR, self harming, self hugging, aggression RAI1 with 3.7Mb common deletion, transcriptional regulator
39
Describe Potocki-Lupski Syndrome
17p11.2 Microduplication FTT, hypotonia, CHD, sleep disordered breathing, palatal abnormalities Vary in size, mostly 3.7Mb - 60% reciprocal dup of SMS
40
What disorders are associated with 17p12 deletions and duplications?
Deletion - HNPP Numbness of nerves following pressures, pes cavus, scoliosis and deafness Duplication CMT1A Increased level of PMP22 in compact myelin of peripheral nerves, slow nerve conductance velocity, motor neuropathy, muscle weakness and atrophy, weakness of hands and sensory loss
41
Describe the Neurofibromatosis 1 Microdeletion
17q11.2 Early onset multiple fibromas MR Dysmorphism Increased risk of malignant peripheral nerve sheath tumours Mediated by interchromasomal meiotic NAHR between LCRs NF-REP1a and NF-REP1c - 14 genes
42
What is the locus for RCAD/MODY5?
17q12 deletion
43
Give 3 clinical features of Edwards Syndrome
``` Trisomy 18 IUGR Low set ears Prominent occiput Micrognathia Cleft lip Rockerbottom feet Overlapping fingers ```
44
Describe Alagille Syndrome
Haploinsufficiency of JAG1 Chronic cholestasis, CHD, minor vertebral segmental anomalies, dysmorphic AD - variable expression
45
Discuss the 2 forms of Ring 20 chromosome
Post-zygotic telomere-telomere fusion -mosaic, no deletion, seizures, devdel, dysmorphism Deletion of p&q telomeres - non-mosaic, seizures, devdel, dysmorphism - Not recurrent bps
46
What is the imprinted region on chromosome 20?
GNAS locus at 20q13.32
47
What are the imprinted genes within the GNAS locus?
Gnasx1 and Nespas - PATERNAL | Nesp - MATERNAL
48
What are deletions of the GNAS locus associated with?
Severe pre and postnatal growth retardation, intractable feeding difficulties, abnormal adipose tissue
49
Give the origins of non-disjuntion trisomy 21
70% maternal M1 20% maternal M2 5% paternal M1 and M2 5% Mitotic
50
Give two mechanisms giving rise to mosaic trisomy 21
Anaphase lag in trisomic fetus | Non-disjuntion in a normal conceptus
51
Give 3 clinical features of Down Syndrome
Mental retardation (affects all but rarely severe) Characteristic facial features (flat facies, epicanthic folds, upward slanting palpebral fissues, protruding tongue) Soft markers - single palmar crease, clinodactyly, sandal gap Infantile hypotonia
52
Give 3 increased risks seen in patients with Down Syndrome
Cardiac abn's (ASD/VSD) Transient leukaemia Early onset Alzheimer disease
53
What is the Down Syndrome susceptibility locus?
21q22.3
54
How many LCRs are found on chromosome 22?
8 - LCR22-A --> LCR22-H
55
What is the most common microdeletion in humans?
22q11.2 Deletion - DGS/VCFS
56
Give 3 clinical features of Velocardiofacial Syndrome
Palatal insufficiency Dysmorphism Cardio-vascular abnormalities
57
Give 3 clinical features of Di George Syndrome
``` Outflow tract defects of the heart (eg TOF) Hypocalcaemia (parathyroid hypoplasia) Recurrent infections (deficient T-cells - hypoplasia/absence of thymus) ```
58
What is the most common deletion seen in DGS/VCFS?
3Mb LCR22-A --> D
59
Describe role of TBX1 in DGS/VCFS
Involved in embryonic differentiation - largely responsible for physical malformations seen
60
Name 2 genes playing role in outflow tract morphogenesis in DGS
CRKL and MAPK1
61
What is the gene hat causes the physical malformations seen in 22q11.2 deletion syndrome?
TBX1 - role in embryonic differentiation
62
What role do CRKL and MAPK1 carry out? Name the disorder they are associated with.
Regulate heart outflow tract morphogenesis - associated with 22q11.2 deletion syndrome
63
Describe the 22q11.2 Duplication syndrome
Mild learning difficulties, heart defects, velopharyngeal insufficiency +/- cleft palate Often seen in normal individuals/inherited Similar aetiology to deletions
64
Give 3 clinical features of the Distal 22q11.2 deletions
Devdel, short stature, premature birth, dysmorphism
65
What are the LCR bp's of the distal 22q11.2 deletion? What is the key gene involved?
LCR22-F --> G - SMARCB1
66
What risk does a deletion of SMARCB1 confer?
Increased risk of rhabdoid tumours
67
Give 3 clinical features of Cat-Eye Syndrome
Ocular coloboma, preauricular skin tags and pits, anal anomalies, cardiovascular defects, dysmorphic features, various levels of MR
68
Describe the 2 types of supernumerary marker seen in Cat-Eye Syndrome
Type 1 - marker has both bps at proximal LCR22-A and don't contain DG/VCFS region Type 2 - one or both bps in distal LCR22-D and contains 1 or 2 copies of the DG/VCFS region
69
What is the locus for Phelan-McDermid Syndrome?
Distal 22q13 deletion
70
Give 3 clinical features of Phelan-McDermid Syndrome
Significant speech delay, hypotonia, dysmorphism, autism
71
What is the candidate gene for the neurological features of Phelan-McDermid Syndrome?
SHANK3
72
What disorder is ARSA typically deleted in?
Phelan-McDermid Syndrome
73
Describe Swyer Syndrome
Complete gonadal dysgenesis - 46,XY - normal female external genitalia and completely under-developed 'streak' gonads
74
What consideration must be given in 46,XY females?
Increased risk of gonadoblastoma in streak gonads
75
Give 3 clinical features of Klinefelter Syndrome
Hypogonadism, reduced fertility/infertility, reduced testosterone/endocrine function, gynaecomastia, small testes, long arms/legs, tall stature
76
Give 3 clinical features that may be seen in XYY syndrome
May be taller than average, may see LD, delayed speech& language, delayed motor skills and hypotonia
77
Name 3 genes on the Y chrm where microdeletions commonly lead to a phenotype
AZF, RBM, DAZ1-4, SPGY and TSPY
78
Give 3 clinical features of Turner Syndrome
Short stature, high palate, short & webbed neck, early loss of ovarian funct, lymphedema of hands/feet, hypoplastic widely spaced nipples
79
What is the common mechanism leading to Turner Syndrome?
Non-disjunction in the father
80
What happens in oocytes in patients with Turner Syndrome?
They undergo apoptosis at an increased rate - often mostly gone by age 2
81
What is the location of SHOX and what is its role?
Xp22.33/Yp11.3 - role in bone development and growth
82
Give 3 clinical features that may be seen in a patient with Trisomy X
Tall stature, epicanthic folds, hypotonia and clinodactyly - also see seizures, renal & genitourinary abns, POF
83
What is the most common reciprocal translocation that isn't a Robertsonian translocation?
t(11;22)(q23;q11)
84
What syndrome can arise from t(11;22)(q23;q11)
Emanuel Syndrome
85
Name 3 clinical features of Emanuel Syndrome
Profound MR, preauricular skin tags, conotruncal heart defects, hypotonia, devdel, microcephaly, micrognathia, cleft palate
86
What mediates the formation of t(11;22)(q23;q11)?
Palindromic AT rich regions - PATRR
87
What segregation leads to Emanuel segregation?
3:1 segregation

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