20.03.20 Microdeletions/microduplication syndromes

Question 1

What are microdeletions/duplications

Answer 1

Loss or gains of a portion of chromosome (<5-10Mb)

Question 2

What two types of microdeletion/duplication syndrome (MMSs) are there

Answer 2

• 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.

Question 3

What is the common basis for MMS

Answer 3

• 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

Question 4

Different types of NAHR

Answer 4

• 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.

Question 5

What are NAHR hotpots

Answer 5

• Positions within LCRs where cross overs preferentially occur.
• Usually in regions of identical nucleotide sequence.

Question 6

What is minimal efficient processing segment (MEPS)

Answer 6

• 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)

Question 7

Why are more microdeletions are reported than microduplications

Answer 7

• 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.

Question 8

What factors influence variable expressivity and reduced penetrance in microdeletions/duplications

Answer 8

• 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)

Question 9

Example of reciprocal microdeletion/duplication syndromes

Answer 9

• 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

Question 10

Review of CMT1A

Answer 10

• 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

Question 11

Review of HNPP

Answer 11

• 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.

Question 12

Describe another 2 disorders caused by either deletion/duplication of 17p11.2

Answer 12

• Smith-Magenis syndrome

- Potocki-Lupski syndrome

Question 13

Review Smith-Magenis syndrome

Answer 13

• 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

Question 14

Review Potocki-Lupski syndrome

Answer 14

• Mild intellectual disability, autistic features, hypotonia, failure to thrive.
• Duplications of 17p11.2 (60% cases)

Question 15

Review of Williams syndrome

Answer 15

• 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.

Question 16

Review of PWS

Answer 16

• 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)

Question 17

Review of AS

Answer 17

• 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

Question 18

Review DiGeorge/ Velocardiofacial syndrome

Answer 18

• 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.

Question 19

Review Miller-Dieker syndrome

Answer 19

• Del 17p13.3
• Lissencephaly, microcephaly, severe mental retardation
• Usually de novo, but 20% have inherited from a parent who carries a balanced chromosome rearrangement.

Question 20

Examples of terminal microdeletion syndromes

Answer 20

• Wolf-Hirschhorn syndrome (WHS)

- Cri-du-chat syndrome

Question 21

Review Wolf-Hirschhorn syndrome

Answer 21

• 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

Question 22

Review Cri-du-chat syndrome

Answer 22

• 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

Question 23

Methods to detect MMS

Answer 23

• Genomic microarrays
• Fluorescence in situ hybridization
• quantitative PCR
• Multiplex ligation-dependent probe amplification

Question 24

Databases for MMSs

Answer 24

• Database of genomic variants (DGV)

- Chromosome anomaly collection

Question 25

Catalogues of pathological imbalances

Answer 25

• Decipher (database of chromosomal imbalance and phenotype in humans using ensemble resources)
• ECARUCA (European cytogeneticists association register of unbalanced chromosome aberrations)
• HGMD