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Genetics Of Learning Disorders > Application Of Arrays In A Clinical Context > Flashcards

Application Of Arrays In A Clinical Context Flashcards

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Biology 101 flashcards
1
Q

What is a DNA microarray?

A

A collection of DNA probes attached to a solid surface that allow simultaneous examination of copy number changes within a DNA sample

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2
Q

Outline the steps involved in microarray processing

A
  1. DNA extraction and digestion
  2. Reference DNA labelled with Cy3, test DNA labelled with Cy5
  3. Equal amounts of both DNAs are combined and hybridised to the slide
  4. The slide is scanned and an image produced. Software translates this image to a profile
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3
Q

What are the three basic types of array used for assessing copy number variants in cytogenetics?

A
  1. BAC arrays: amplified BAC DNA spotted into glass slides, effectively the same as multiple FISH probes. Resolution ~0.5-1Mb
  2. Oligo arrays: custom oligos spotted onto glass slides. Higher resolution (~100-200kb). Increased coverage improves resolution
  3. SNP arrays: detect single nucleotide variation. Allele specific oligonucleotide probes used to detect polymorphism
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4
Q

What are the five main clinical applications of microarray?

A
  1. Constitutional cytogenetics
  2. Prenatal diagnosis
  3. Solid tumours
  4. Products of conception
  5. Malignancies
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5
Q

What three key processes does arrayCGH enable?

A
  • Rapid and accurate screening for subtle DNA copy number changes along whole genome that karyotyping can’t detect
  • Precise delineation of deleted/duplicated segments in order to investigate link between presence of one unbalanced rearrangement and observed phenotype
  • Del/dup breakpoint mapping
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6
Q

What are commonly used selection criteria for array analysis?

A
  1. Prenatal onset abnormal growth pattern
  2. Global Dev delay and LD
  3. Behavioural problems
  4. One or more congenital malformations
  5. Craniofacial dysmorphism
  6. Family history of recurrent miscarriage, LD or congenital malformations
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7
Q

What are the two major limitations of arrayCGH?

A
  1. Cannot detect balanced chromosome rearrangements such as reciprocal translocations and inversions. The order and orientation of the rearranged segments involved cannot be determined
  2. May not detect mosaicism where the proportion of abnormal cells is ???
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8
Q

What are 6 considerations for clinical interpretation of CNVs?

A
  1. Comparison of CNV with internal and external databases
  2. Association of CNV with well established syndromes
  3. Genomic content
  4. CNV size
  5. Follow up studies
  6. Inheritance of CNV
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9
Q

Provide further information on comparison of the CNV with internal and external databases

A
  • Frequency of CNV in internal (local) database
  • Comparison with Database of Genimic Variants (DGV)
  • Association of CNV with known syndromes (e.g. DECIPHER, PubMed, OMIM, ISCA etc)
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10
Q

What is involved with consideration of the genomic content in the CNV?

A
  • Are there genes relevant to the phenotype?
  • Are the genes dosage sensitive?
  • If there is a loss/gain is a phenotype associated with haploinsufficiency/triplosensitivity?
  • Single copy deletions of a recessive gene may only suggest carrier status, depending on mutation on the other homologue
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11
Q

Why is CNV size not always important?

A
  • Not always large CNVs that are pathogenic - can have very small pathogenic changes
  • Some large euchromatin chromosomal variants that are not pathogenic
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12
Q

What follow up studies can be conducted for an abnormal CNV.

A
  • Approx 25% of referrals have imbalances which require parental bloods to assist interpretation (unknown significance)
  • 15-20% of these turn out to be de novo and depending on gene content may be causative
  • parental bloods are tested to ascertain recurrence risk: may carry a balanced translocation or can be Asymptomatic in cases of pathogenic CNVs with reduced Penetrance
  • FISH is preferable as it gives positional information
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13
Q

Are familial CNVs clinically relevant?

A
  • Syndromic CNVs often have reduced Penetrance and variable expressivity
  • de novo CNVs are considered more likely to be causal
  • inherited copy no. gains could also be causal as can often be inherited from an Asymptomatic parent
  • phenotype may depend on co-occurrence of other CNVs and mutations
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14
Q

What are the 4 essential steps to classify a CNV as benign?

A
  1. Comparison with DGV
  2. > 1% freq. and 100% coverage with same gene content and similar dosage in at least one publication
  3. Sex for X-linked CNVs
  4. Comparison with internal database >3% and preferably 100% coverage
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15
Q

Give two example categories of incidental findings

A
  1. Late-onset conditions

2. Cancer susceptibility genes

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16
Q

What are SNP arrays capable of detecting in the context of prenatal diagnosis?

A

Tripoloidy and complete moles

17
Q

Are arrays as good as karyotyping for prenatal diagnosis?

A

Arrays will identify almost all of the abnormalities that are identified by fetal karyotyping and may identify additional specific genetic diseases

18
Q

What are the BSHG recommendations for indications of prenatal array testing?

A
  • one or more structural anomalies identified on ultrasound scan
  • isolated nuchal translucency NT=3.5mm when crown rump length measures from 45-84mm (approx. 11 weeks 0 days to 13 weeks 6 days)
  • fetuses with sex chromosome aneuploidy that is unlikely to explain ultrasound finding
19
Q

What are the five main types of variant to be reported in a prenatal setting?

A
  1. Pathogenic variants relevant to the referral indication
  2. Neurosusceptiblity loci associated with increased incidence of anomalies detectable on scan
  3. High Penetrance neurosusceptibility loci that are associated with a risk of severe phenotype
  4. Deletion of a known cancer predisposition gene e.g. BRCA1
  5. Deletion of the dystrophin gene in a female fetus, again to allow mother to be tested for carrier status
20
Q

What are the incidental array findings not to be reported in a prenatal setting?

A
  1. Any finding that is not linked to potential phenotypes for the pregnancy or has no clinically actionable consequence for the child or family in the future
  2. Variants of uncertain significance that cannot be linked to a potential phenotype on the basis of the genes involved
  3. Low Penetrance neurosusceptibility loci and unsolicited variants
  4. Heterozygous deletion of recessive genes that cannot be linked to the presenting phenotype
21
Q

Provide more details on the analysis of products of conception array testing

A
  • Used to investigate the aetiology of the miscarriage
  • indicated in women suffering a first trimester fetal loss
  • particularly relevant in couples with recurrent miscarriages and those with a miscarriage after assisted reproductive technology cycle
22
Q

What are the advantages of analysing products of conception by array?

A
  • tissue culture is not required
  • successful results in >98% of analysed samples
  • analysis to rule out maternal cell contamination
  • SNP arrays can detect Tripoloidy and complete mole
  • can detect unbalanced rearrangements that derive from a balanced parental rearrangement that would have recurrence risk for the parents
23
Q

What are the applications of arrays in haematological malignancies?

A
  • can identify wide spectrum of CNVs in AML-ALL-MM patients
  • copy neutral loss of heterozygosity are identified
  • chromothripsis could be identified (thousands of chromosomal rearrangements occurring in a single localised event)
  • genetic alterations allow to define subgroups with worse prognosis and rapidly stratify treatment
24
Q

What are the main applications of arrays in clinical management of tumours?

A
  • Reveal copy number markers for cancer predisposition and choice of treatment
  • Monitor cancer progression and can distinguish between mild and metastatic censorious lesions
  • Measure the DNA copy number of oncogenes and TSGs
  • Identify and understand the genes that are involved in cancer and help to design therapeutic drugs
25
Q

What are the advantages of microarray compared to NGS?

A
  • generally considered easier to use and analyse the data
  • more economical
  • yield higher throughput

Genetics Of Learning Disorders (11 decks)

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