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FRC Path 2023 > Chromosome Disorders > Flashcards

Chromosome Disorders Flashcards

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 Wolf-Hirschhorn syndrome (WHS)? Name 3 clinical features.

A

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

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4
Q

Describe Thrombocytopenia-absent radius (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 Von Hippel-Lindau syndrome (VHL)

A

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

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8
Q

How can Wolf-Hirschhorn be inherited?

A

t(4;8) - Maternal
Other chrm rearrangements - Paternal

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9
Q

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

A

5p15.3-p15.2
High pitched cry
Microcephaly
Severe psychomotor and mental retardation
Cardiac abn’s

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10
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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11
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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12
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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13
Q

Describe the clinical significance of UPD7

A

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

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14
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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15
Q

Give 3 clinical features of mosaic trisomy 8

A

Skeletal abnormalities
Hypertelorism
Cardiac/renal abnormalities
Predisposition to haematological malignancy

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16
Q

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

A

OR gene clusters on 8p –>unequal crossing over

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17
Q

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

A
  1. inv dup del (8p) - DUP thought to contribute most to pheno - devel, speech delay, hypotonia, microcephaly
  2. 8p23.1 micdel - devdel, behavioural prob’s, CHD (GATA4)
  3. 8p23.1 micdup - devdel, mild dysmorphism, cardiac defects
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18
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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19
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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20
Q

Describe WAGR (Wilms tumor, Aniridia, Genitourinary anomalies, and intellectual disability)

A

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

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21
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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22
Q

Give 3 clinical features of Noonan Syndrome

A

CHD - Congenital heart defects (esp pulmonary valvular stenosis),
short stature,
webbed neck,
devdel

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23
Q

Give 3 clinical features of Patau Syndrome

A

Trisomy 13
Congenital heart defects
Holoprosencephaly
Polydactyly
Cleft lip and palate

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24
Q

Describe the 13q14 Deletion Syndrome

A

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

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25
Q

Describe maternal UPD 14 - give the maternally expressed genes

A

Pre and postnatal growth retardation
low to normal intellectual dev
subtle dysmorphism
GTL2, PEG11, RTL1

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26
Q

Describe paternal UPD 14 - give the paternally expressed genes

A

Polyhydramnios –> early labour
Thoracic and abdominal wall defects
Moderate/severe LD
Subtle dysmorphism
DLK1, DI03, RTL1

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27
Q

Describe the 15q11.2 Deletion syndrome in as much details as you can

A

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

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28
Q

Describe the 15q13.3 Deletion syndrome

A

BP4-BP5 (rarely BP3-BP5)
CHRNA7 plays role in neurodevelopment - haploinsufficiency linked to phenotype
incomplete penetrance

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29
Q

Give some key points to consider when assessing idic(15)

A

PWACR must be present to cause phenotype
Studies suggest parent of origin significant - MATERNAL clinically significant, PATERNAL ?benign?

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30
Q

Describe the 16p11.2 region

A

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

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31
Q

Give 3 clinical features of 16p11.2 deletion syndrome

A

Speech/language delay
Cognitive impairment
Motor delay
Seizures
Behavioural prob’s
Congenital abn’s
Autism
Macrocephaly

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32
Q

Give 3 clinical features of 16p11.2 duplication syndrome

A

Microcephaly
Motor delay
ADHD
Seizures

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33
Q

Describe the 16p11.2-p12.2 Microdeletion syndrome

A

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?

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34
Q

Give the gene, location and 3 clinical features of Rubinstein-Taybi syndrome

A

CREBBP - 16p13.3
Microcephaly
MR
CHD
Increased risk tumour development

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35
Q

Give the key gene, location and 3 clinical features of Miller Dieker Syndrome

A

PAFAH1B1 - 17p13.3 (258kb critical region)
Lissencephaly
Microcephaly
Seizures
Severe MR
Rarely survive beyond childhood

36
Q

How many classes of 17p13.3 microduplication syndrome are there?

A

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

37
Q

Describe Smith-Magenis Syndrome

A

17p11.2 Microdeletion
Mild/moderate MR, self harming, self hugging, aggression
RAI1 with 3.7Mb common deletion, transcriptional regulator

38
Q

Describe Potocki-Lupski Syndrome

A

17p11.2 Microduplication
FTT, hypotonia, CHD, sleep disordered breathing, palatal abnormalities
Vary in size, mostly 3.7Mb - 60% reciprocal dup of SMS

39
Q

What disorders are associated with 17p12 deletions and duplications?

A

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

40
Q

Describe the Neurofibromatosis 1 Microdeletion

A

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

41
Q

What is the locus for RCAD/MODY5?

A

17q12 deletion

42
Q

Give 3 clinical features of Edwards Syndrome

A

Trisomy 18
IUGR
Low set ears
Prominent occiput
Micrognathia
Cleft lip
Rockerbottom feet
Overlapping fingers

43
Q

Describe Alagille Syndrome

A

Haploinsufficiency of JAG1
Chronic cholestasis, CHD, minor vertebral segmental anomalies, dysmorphic
AD - variable expression

44
Q

Discuss the 2 forms of Ring 20 chromosome

A

Post-zygotic telomere-telomere fusion
-mosaic, no deletion, seizures, devdel, dysmorphism

Deletion of p&q telomeres
-non-mosaic, seizures, devdel, dysmorphism
-Not recurrent bps

45
Q

What is the imprinted region on chromosome 20?

A

GNAS locus at 20q13.32

46
Q

What are the imprinted genes within the GNAS locus?

A

Gnasx1 and Nespas - PATERNAL
Nesp - MATERNAL

47
Q

What are deletions of the GNAS locus associated with?

A

Severe pre and postnatal growth retardation, intractable feeding difficulties, abnormal adipose tissue

48
Q

Give the origins of non-disjuntion trisomy 21

A

70% maternal M1
20% maternal M2
5% paternal M1 and M2
5% Mitotic

49
Q

Give two mechanisms giving rise to mosaic trisomy 21

A

Anaphase lag in trisomic fetus
Non-disjuntion in a normal conceptus

50
Q

Give 3 clinical features of Down Syndrome

A

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

51
Q

Give 3 increased risks seen in patients with Down Syndrome

A

Cardiac abn’s (ASD/VSD)
Transient leukaemia
Early onset Alzheimer disease

52
Q

What is the Down Syndrome susceptibility locus?

A

21q22.3

53
Q

How many low copy repeats (LCRs) are found on chromosome 22?

A

8 - LCR22-A –> LCR22-H

54
Q

What is the most common microdeletion in humans?

A

22q11.2 Deletion - DGS/VCFS

55
Q

Give 3 clinical features of Velocardiofacial Syndrome

A

Palatal insufficiency
Dysmorphism
Cardio-vascular abnormalities

56
Q

Give 3 clinical features of Di George Syndrome

A

Outflow tract defects of the heart (eg TOF)
Hypocalcaemia (parathyroid hypoplasia)
Recurrent infections (deficient T-cells - hypoplasia/absence of thymus)

57
Q

What is the most common deletion seen in Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS)?

A

3Mb LCR22-A –> D

58
Q

Describe role of TBX1 in DGS/VCFS

A

Involved in embryonic differentiation - largely responsible for physical malformations seen

59
Q

Name 2 genes playing role in outflow tract morphogenesis in DGS

A

CRKL and MAPK1

60
Q

What is the gene that causes the physical malformations seen in 22q11.2 deletion syndrome?

A

TBX1 - role in embryonic differentiation

61
Q

What role do CRKL and MAPK1 carry out? Name the disorder they are associated with.

A

Regulate heart outflow tract morphogenesis - associated with 22q11.2 deletion syndrome

62
Q

Describe the 22q11.2 Duplication syndrome

A

Mild learning difficulties,
heart defects,
velopharyngeal insufficiency +/- cleft palate
Often seen in normal individuals/inherited
Similar aetiology to deletions

63
Q

Give 3 clinical features of the Distal 22q11.2 deletions

A

Devdel, short stature, premature birth, dysmorphism

64
Q

What are the Low copy repeats (LCR) bp’s of the distal 22q11.2 deletion? What is the key gene involved?

A

LCR22-F –> G - SMARCB1

65
Q

What risk does a deletion of SMARCB1 confer?

A

Increased risk of rhabdoid tumours

66
Q

Give 3 clinical features of Cat-Eye Syndrome

A

Ocular coloboma, preauricular skin tags and pits, anal anomalies, cardiovascular defects, dysmorphic features, various levels of MR

67
Q

Describe the 2 types of supernumerary marker seen in Cat-Eye Syndrome

A

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

68
Q

What is the locus for Phelan-McDermid Syndrome?

A

Distal 22q13 deletion

69
Q

Give 3 clinical features of Phelan-McDermid Syndrome

A

Significant speech delay, hypotonia, dysmorphism, autism

70
Q

What is the candidate gene for the neurological features of Phelan-McDermid Syndrome?

A

SHANK3

71
Q

What disorder is ARSA typically deleted in?

A

Phelan-McDermid Syndrome

72
Q

Describe Swyer Syndrome

A

Complete gonadal dysgenesis - 46,XY - normal female external genitalia and completely under-developed ‘streak’ gonads

73
Q

What consideration must be given in 46,XY females?

A

Increased risk of gonadoblastoma in streak gonads

74
Q

Give 3 clinical features of Klinefelter Syndrome

A

Hypogonadism, reduced fertility/infertility, reduced testosterone/endocrine function, gynaecomastia, small testes, long arms/legs, tall stature

75
Q

Give 3 clinical features that may be seen in XYY syndrome

A

May be taller than average, may see LD, delayed speech& language, delayed motor skills and hypotonia

76
Q

Name 3 genes on the Y chrm where microdeletions commonly lead to a phenotype

A

AZF, RBM, DAZ1-4, SPGY and TSPY

77
Q

Give 3 clinical features of Turner Syndrome

A

Short stature, high palate, short & webbed neck, early loss of ovarian funct, lymphedema of hands/feet, hypoplastic widely spaced nipples

78
Q

What is the common mechanism leading to Turner Syndrome?

A

Non-disjunction in the father

79
Q

What happens in oocytes in patients with Turner Syndrome?

A

They undergo apoptosis at an increased rate - often mostly gone by age 2

80
Q

What is the location of SHOX and what is its role?

A

Xp22.33/Yp11.3 - role in bone development and growth

81
Q

Give 3 clinical features that may be seen in a patient with Trisomy X

A

Tall stature, epicanthic folds, hypotonia and clinodactyly - also see seizures, renal & genitourinary abns, POF

82
Q

What is the most common reciprocal translocation that isn’t a Robertsonian translocation?

A

t(11;22)(q23;q11)

83
Q

What syndrome can arise from t(11;22)(q23;q11)

A

Emanuel Syndrome

84
Q

Name 3 clinical features of Emanuel Syndrome

A

Profound MR, preauricular skin tags, conotruncal heart defects, hypotonia, devdel, microcephaly, micrognathia, cleft palate

85
Q

What mediates the formation of t(11;22)(q23;q11)?

A

Palindromic AT rich regions - PATRR

FRC Path 2023 (15 decks)

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