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3:  Modes of inheritance and constitutional genetics > 21. Use of microarray for detection of idiopathic learning difficulties  > Flashcards

21. Use of microarray for detection of idiopathic learning difficulties  Flashcards

1
Q

What types of referral are received for microarray?

A
  1. Postnatal blood for dev delay, congenital abnormalities
  2. Tissues from TOP or pregnancy loss (after QF-PCR pre-screen)
  3. Amnio/CVS due to abnormal USS (after QF-PCR pre-screen)
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2
Q

What are LCRs?

A

Low copy repeats aka segmental duplications

Highly homologous sequences of >95% homology, >1kb in size

Mediate NAHR if in close proximity leading to dels/dups

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3
Q

How does a SNP array work?

A

Solid surface containing 1000s of unique probe that hybridise adjacent to SNP

Fragmented DNA hybridises to probe - single base extension to determine genotype of SNP based on colour of fluorescence

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4
Q

What is the resolution of a SNP array?

A

Varies across genome

Illumina 850k array has 850k probes across the genome - enriched for >3000 dosage sensitive genes, with lower resolution backbone

Average spacing 1kb in targeted genes, 5kb in backbone

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5
Q

What are the two metrics used in SNP array analysis?

A
  1. Log ratio - total intensity of both fluorescent signals combined
  2. B allele frequency - colour of fluorescence emitted at each SNP
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6
Q

Why are there 2 measures of copy number in SNP array analysis?

A

Independent measures used to corroborate one another

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7
Q

What is a cluster file?

A

Reference file

Generated from cohort of normal patient samples, used to compare test sample against

Captures normal variation in population, operators, sample types

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8
Q

What formula is used to determine the BAF?

A

B / (A+ B)

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9
Q

What BAF pattern is seen for a normal copy number?

A

3 clusters at 1, 0.5 and 0

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10
Q

What BAF pattern is seen for a het deletion?

A

2 clusters at 1 and 0

No heterozygous SNPs so no cluster at 0.5

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11
Q

How does a hemi/hom deletion appear on SNP array?

A

Copy number 0 on log track

Random allocation of SNPs on BAF track

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12
Q

What BAF pattern is seen for a het duplication?

A

4 clusters at 0, 0.33, 0.66 and 1

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13
Q

How does mosaic CNV appear on SNP array?

A

Small loss/gain on log ratio

Duplication pattern on BAF track - het ratios differ from 0.5 depending on level of mosaicism

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14
Q

How does triploidy appear on SNP array?

A

Duplication pattern for all of every chromosome

Not visible on log ratio as normalised for entire chromsome

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15
Q

What indicates consanguinity?

A

Multiple regions of LOH affecting many chromosomes across the whole genome

Total autosomal LOH of >1.5% = consanguinity

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16
Q

How does UPD appear on SNP array?

A

LOH on a single chromosome (deletion pattern)

Log ratio normal

17
Q

What techniques are used to follow up array and what are their advantages & disadvantages?

A

FISH to confirm - provides positional info but CNV may be below resolution

Targeted array if below resolution but no positional info

MLPA if kit available

Karyotyping if balanced rearrangement suspected

18
Q

What are the advantages of SNP array?

A

High resolution than karyotyping - higher pick up rate

Amenable to automation and high throughput

BAF track can detect consanguinity therefore increased risk of AR conditions and UPD therefore additional diagnoses

19
Q

What type of UPD can SNP array detect?

A

Isodisomy only

Heterodisomy if parents are also tested

20
Q

What are the disadvantages of SNP array?

A
  1. Can’t detect balanced rearrangements
  2. Can’t give positional info
  3. Increased detection of VUSs –> parental anxiety, counselling
  4. Risk of incidental findings (BRAC2 deletion, DMD CNVs)
21
Q

What is the purpose of testing for dev delay/LD?

A

Provides prognostic info, direct clinical care & educational needs

Allow for future prenatal diagnosis

22
Q

What evidence is used to determine the pathogenicity of a CNV?

A

Number of genes involved

Known haploinsufficient or triplosensitive genes involved?

Previous de novo cases, taking into account phenotypic overlap

Segregation

Case-control data

3:  Modes of inheritance and constitutional genetics (19 decks)

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