Chromosome Disorders Flashcards
What mediates the deletions/duplications on 1q21?
Fully describe the class 2 deletions of this region.
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
What are the clinical features of 1p36 deletion syndrome?
Developmental delay
Slow closing fontanelle
Hypotonia
Delayed/absent speech
Growth retardation
Eye defects
What is the critical locus for Wolf-Hirschhorn syndrome (WHS)? Name 3 clinical features.
4p16.3
Typical facial appearance
Growth delay
Seizure
Mental retardation
Describe Thrombocytopenia-absent radius (TAR)
Incomplete penetrance, absent radius with thumbs present, thrombocytopenia
RBM8A gene - ? second hit model, compound inheritance model
Where is NRXN1? Describe deletion syndrome
2p16.3
Moderate/severe ID, psychiatric disorders, severe language delay
Reduced penetrance and variable expressivity
What is the locus and gene for Mowat-Wilson syndrome? Name 2 clinical features
2q22 - ZEB2
Hirshprung disease
Genitourinary anomalies
Characteristic facial features
Give me 3 facts about Von Hippel-Lindau syndrome (VHL)
3p25
AD familial cancer syndrome
Renal cell carcinomas in approx 70%
How can Wolf-Hirschhorn be inherited?
t(4;8) - Maternal
Other chrm rearrangements - Paternal
Critical region for Cri-du-chat syndrome and 3 clinical features
5p15.3-p15.2
High pitched cry
Microcephaly
Severe psychomotor and mental retardation
Cardiac abn’s
Gene and region for Sotos and 3 clinical features
NSD1 on 5q35
Excessive physical growth 2-3yrs of age
Macrocephaly
Behavioural problems
Tell me 3 facts about Cornelia de Lange Syndrome
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
What is the clinical significance of UPD6?
Paternal UPD6 / patUPD 6q24
Neonatal benign transient diabetes - often resolved by 3yrs of age
Describe the clinical significance of UPD7
Maternal UPD - IUGR, retarded bone age, relative macrocephaly, characteristic facial features
What is the critical region for Williams Syndrome? Give 3 clinical features
7q11.23 - ELN
Supravalvular aortic stenosis
Hypercalcaemia
Hypotonia
Devdel
Give 3 clinical features of mosaic trisomy 8
Skeletal abnormalities
Hypertelorism
Cardiac/renal abnormalities
Predisposition to haematological malignancy
What gives rise to abnormalities seen on 8p23.1?
OR gene clusters on 8p –>unequal crossing over
Give 3 CNVs at 8p23.1 and their clinical features
- 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
Describe Roberts Syndrome
Pseudothalidomide Synrome, rare AR, premature centrome separation and heterochromatin repulsion - ESCO2
Massive limb abnormalities, cleft lip and palate, microcephaly
Describe CHARGE syndrome
8q21 -CHD7
Coloboma, Heart defects, choanal Atresia, Retarded growth and development, Genital abnormalities and Ear anomalies
Describe WAGR (Wilms tumor, Aniridia, Genitourinary anomalies, and intellectual disability)
11p13 deletion syndrome
Wilms tumour, Aniridia, Genitourinary anomalies, mental Retardation
WT1 (Wilms Tumour supressor gene)
PAX6 (oculogenesis)
Describe the formation of the chromosome abnormality in Pallister-Killian Syndrome
Mosaic tetrasomy 12p/+iso(12p)
Non-disjuntion at Meiosis 2 followed by centromere misdivision and formation of the isochromosome
Give 3 clinical features of Noonan Syndrome
CHD - Congenital heart defects (esp pulmonary valvular stenosis),
short stature,
webbed neck,
devdel
Give 3 clinical features of Patau Syndrome
Trisomy 13
Congenital heart defects
Holoprosencephaly
Polydactyly
Cleft lip and palate
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
Describe maternal UPD 14 - give the maternally expressed genes
Pre and postnatal growth retardation
low to normal intellectual dev
subtle dysmorphism
GTL2, PEG11, RTL1
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
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
Describe the 15q13.3 Deletion syndrome
BP4-BP5 (rarely BP3-BP5)
CHRNA7 plays role in neurodevelopment - haploinsufficiency linked to phenotype
incomplete penetrance
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?
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
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
Give 3 clinical features of 16p11.2 duplication syndrome
Microcephaly
Motor delay
ADHD
Seizures
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?
Give the gene, location and 3 clinical features of Rubinstein-Taybi syndrome
CREBBP - 16p13.3
Microcephaly
MR
CHD
Increased risk tumour development
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
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
Describe Smith-Magenis Syndrome
17p11.2 Microdeletion
Mild/moderate MR, self harming, self hugging, aggression
RAI1 with 3.7Mb common deletion, transcriptional regulator
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
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
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
What is the locus for RCAD/MODY5?
17q12 deletion
Give 3 clinical features of Edwards Syndrome
Trisomy 18
IUGR
Low set ears
Prominent occiput
Micrognathia
Cleft lip
Rockerbottom feet
Overlapping fingers
Describe Alagille Syndrome
Haploinsufficiency of JAG1
Chronic cholestasis, CHD, minor vertebral segmental anomalies, dysmorphic
AD - variable expression
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
What is the imprinted region on chromosome 20?
GNAS locus at 20q13.32
What are the imprinted genes within the GNAS locus?
Gnasx1 and Nespas - PATERNAL
Nesp - MATERNAL
What are deletions of the GNAS locus associated with?
Severe pre and postnatal growth retardation, intractable feeding difficulties, abnormal adipose tissue
Give the origins of non-disjuntion trisomy 21
70% maternal M1
20% maternal M2
5% paternal M1 and M2
5% Mitotic
Give two mechanisms giving rise to mosaic trisomy 21
Anaphase lag in trisomic fetus
Non-disjuntion in a normal conceptus
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
Give 3 increased risks seen in patients with Down Syndrome
Cardiac abn’s (ASD/VSD)
Transient leukaemia
Early onset Alzheimer disease
What is the Down Syndrome susceptibility locus?
21q22.3
How many low copy repeats (LCRs) are found on chromosome 22?
8 - LCR22-A –> LCR22-H
What is the most common microdeletion in humans?
22q11.2 Deletion - DGS/VCFS
Give 3 clinical features of Velocardiofacial Syndrome
Palatal insufficiency
Dysmorphism
Cardio-vascular abnormalities
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)
What is the most common deletion seen in Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS)?
3Mb LCR22-A –> D
Describe role of TBX1 in DGS/VCFS
Involved in embryonic differentiation - largely responsible for physical malformations seen
Name 2 genes playing role in outflow tract morphogenesis in DGS
CRKL and MAPK1
What is the gene that causes the physical malformations seen in 22q11.2 deletion syndrome?
TBX1 - role in embryonic differentiation
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
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
Give 3 clinical features of the Distal 22q11.2 deletions
Devdel, short stature, premature birth, dysmorphism
What are the Low copy repeats (LCR) bp’s of the distal 22q11.2 deletion? What is the key gene involved?
LCR22-F –> G - SMARCB1
What risk does a deletion of SMARCB1 confer?
Increased risk of rhabdoid tumours
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
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
What is the locus for Phelan-McDermid Syndrome?
Distal 22q13 deletion
Give 3 clinical features of Phelan-McDermid Syndrome
Significant speech delay, hypotonia, dysmorphism, autism
What is the candidate gene for the neurological features of Phelan-McDermid Syndrome?
SHANK3
What disorder is ARSA typically deleted in?
Phelan-McDermid Syndrome
Describe Swyer Syndrome
Complete gonadal dysgenesis - 46,XY - normal female external genitalia and completely under-developed ‘streak’ gonads
What consideration must be given in 46,XY females?
Increased risk of gonadoblastoma in streak gonads
Give 3 clinical features of Klinefelter Syndrome
Hypogonadism, reduced fertility/infertility, reduced testosterone/endocrine function, gynaecomastia, small testes, long arms/legs, tall stature
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
Name 3 genes on the Y chrm where microdeletions commonly lead to a phenotype
AZF, RBM, DAZ1-4, SPGY and TSPY
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
What is the common mechanism leading to Turner Syndrome?
Non-disjunction in the father
What happens in oocytes in patients with Turner Syndrome?
They undergo apoptosis at an increased rate - often mostly gone by age 2
What is the location of SHOX and what is its role?
Xp22.33/Yp11.3 - role in bone development and growth
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
What is the most common reciprocal translocation that isn’t a Robertsonian translocation?
t(11;22)(q23;q11)
What syndrome can arise from t(11;22)(q23;q11)
Emanuel Syndrome
Name 3 clinical features of Emanuel Syndrome
Profound MR, preauricular skin tags, conotruncal heart defects, hypotonia, devdel, microcephaly, micrognathia, cleft palate
What mediates the formation of t(11;22)(q23;q11)?
Palindromic AT rich regions - PATRR
