20.03.20 Microdeletions/microduplication syndromes Flashcards
1
Q
What are microdeletions/duplications
A
Loss or gains of a portion of chromosome (<5-10Mb)
2
Q
What two types of microdeletion/duplication syndrome (MMSs) are there
A
- Single gene syndromes. Due to loss/gain of a dosage-sensitive gene. Eg. PMP22 in CMT1A/HNPP or NF1 in neurofibromatosis type 1. Neighbouring genes may be involved but are not dosage sensitive.
- Contiguous gene syndromes. Loss/gain of multiple contiguous adjacent genes, some of which are dosage sensitive. e.e. Williams syndrome.
3
Q
What is the common basis for MMS
A
- Low copy repeats (LCRs), i.e. segmental duplications. DNA blocks of 10-400kb with high degree of homology (>97%)
- Non-allelic homologous recombination (NAHR)- between misaligned repeats of the same sequence but different chromosomal location
4
Q
Different types of NAHR
A
- Interchromosomal (between two homologous chromosomes)
- Intrachromosomal (between chromatids of the same chromosome)
- Intrachromatid (on the same chromatid)
- Each type can then be direct, inverted or complex.
5
Q
What are NAHR hotpots
A
- Positions within LCRs where cross overs preferentially occur.
- Usually in regions of identical nucleotide sequence.
6
Q
What is minimal efficient processing segment (MEPS)
A
- The minimal stretch of identity required to enable homologous recombination.
- Length of MEPS can be different between meiosis and mitosis.
- Distance between LCRs could play a role in MEPS length (the larger the distance between LCRs, the longer the MEPS)
7
Q
Why are more microdeletions are reported than microduplications
A
- In theory, for every microdeletion syndrome there should be a reciprocal microduplication syndrome (CMT1A and HNPP)
- Hypothesis- microduplications result in milder phenotype. E.g. trisomy is better tolerated than monosomy.
- Techniques (FISH) are less sensitive to microduplications. Less so for arrays.
8
Q
What factors influence variable expressivity and reduced penetrance in microdeletions/duplications
A
- Variable breakpoints
- Differences in genetic background (presence of additional modifying variants)
- Unmasking of recessive variants on the second allele (or a second hit variant)
- Epigenetic modifications (PWS/AS)
9
Q
Example of reciprocal microdeletion/duplication syndromes
A
- 17p11.2, encompassing PMP22 gene.
- NAHR between two LCRs known as CMT1A-REPs, which share 98.7% sequence identity.
- CMT1A (Charcot Marie-Tooth)= duplications
- HNPP (Hereditary neuropathy with liability to pressure palsies)= deletions
10
Q
Review of CMT1A
A
- Charcot-Marie-Tooth
- Demyelinating peripheral neuropathy characterised by distal muscle weakness and atrophy, pes cavus, sensory loss and slow nerve conduction velocity.
- Caused by duplications of PMP22 (70-80% of CMT1) 17p11.2
- 1 in 10,000
11
Q
Review of HNPP
A
- Hereditary neuropathy with liability to pressure palsies
- Deletion of 17p11.2 which includes PMP22 (80% cases)
- 2-5 per 100,000 (thought to be higher but many have no or few symptoms)
- Milder condition: repeated focal pressure neuropathies such as carpal tunnel syndrome and peroneal palsy with foot drop.
12
Q
Describe another 2 disorders caused by either deletion/duplication of 17p11.2
A
- Smith-Magenis syndrome
- Potocki-Lupski syndrome
13
Q
Review Smith-Magenis syndrome
A
- Distinctive facial features (brachycephaly, broad face), brachydactyly, dev delay, hypotonia in infancy.
- Deletions of 17p11.2 (70% cases) and mutations in RAI1 gene.
- 1:25,000 births.
- Usually de novo
14
Q
Review Potocki-Lupski syndrome
A
- Mild intellectual disability, autistic features, hypotonia, failure to thrive.
- Duplications of 17p11.2 (60% cases)
15
Q
Review of Williams syndrome
A
- Del 7q11.23
- Characterised by supravalvar aortic stenosis, elfin face, connective tissue abnormalities, over friendly personality, mild intellectual disability.
- Contiguous deletion of WBSCR (Williams-Beuren syndrome critical region). Includes ELN gene.
- WBSCR is flanked by LCRs, predisposing it to NAHR.
- 95% have a 1.55Mb deletion, 5% have 1.84Mb.
- Often de novo, however could be inherited from an unaffected parent with a paracentric inversion involving WBSCR.
16
Q
Review of PWS
A
- Prader-Willi syndrome
- hypotonia, feeding difficulties in infancy. Dev delay, insatiable appetite, in childhood.
- 1 in 10,000 to 1 in 15,000
- Due to absence of expression of imprinted genes in the paternally derived PWS/AS region (15q11.2-q13)
- Either due to maternal UPD, paternal deletion (75%), or rarely an imprinting defect
- Contiguous disorder due to the loss of several genes (SNURF-SNRPN, NDN, PWRN1, MAGEL2)
17
Q
Review of AS
A
- Angelman syndrome
- Severe developmental delay, speech impairment, gait ataxia, microcephaly, seizures.
- 1 in 12,000 to 1 in 20,000
- Caused by disruption of maternally imprinted UBE3A in 15q11.2-13.
- 68% have maternal allele deletion
18
Q
Review DiGeorge/ Velocardiofacial syndrome
A
- 22q11.2 deletion.
- Variable phenotype that includes: cardiac defects, cleft palate, learning difficulties, hypocalcemia.
- 1 in 4,000 to 1 in 6,395
- 85% have 3Mb deletion (encompassing 40 genes)
- Majority are de novo, 7% are inherited
- Significant intrafamilial variability.
19
Q
Review Miller-Dieker syndrome
A
- Del 17p13.3
- Lissencephaly, microcephaly, severe mental retardation
- Usually de novo, but 20% have inherited from a parent who carries a balanced chromosome rearrangement.
20
Q
Examples of terminal microdeletion syndromes
A
- Wolf-Hirschhorn syndrome (WHS)
- Cri-du-chat syndrome
21
Q
Review Wolf-Hirschhorn syndrome
A
- Del 4p16.3
- 1 in 50,000
- typical craniofacial features, growth delay, intellectual disability, seizures.
- ~50% have a pure deletion, the rest have an unbalanced translocation
22
Q
Review Cri-du-chat syndrome
A
- Deletions of 5p (between 5p13-5p15.2)
- 1 in 20,000 to 1 in 50,000
- distinctive cat-like cry, dev delay, microcephaly, hypotonia in infancy
- 85% de novo, 15% result of an unbalanced translocation
23
Q
Methods to detect MMS
A
- Genomic microarrays
- Fluorescence in situ hybridization
- quantitative PCR
- Multiplex ligation-dependent probe amplification
24
Q
Databases for MMSs
A
- Database of genomic variants (DGV)
- Chromosome anomaly collection
25
Catalogues of pathological imbalances
- Decipher (database of chromosomal imbalance and phenotype in humans using ensemble resources)
- ECARUCA (European cytogeneticists association register of unbalanced chromosome aberrations)
- HGMD
