20.03.21 Use of microarray for detection of idiopathic learning difficulties

Question 1

What is developmental delay and intellectual disability

Answer 1

• Significant impairment of cognitive and adaptive functions
• Affects 1-3% of population.
• Chromosomal and genetic disorders account for 30-40% of moderate to severe DD cases.

Question 2

Why is providing a diagnosis important

Answer 2

• Help prognostic information
• Directs clinical care and educational needs.
• Identify support groups for patients and their families
• Allow future prenatal diagnosis

Question 3

What testing methodologies are used

Answer 3

• Array CGH has replaced conventional karyotyping as a first line test in children/adults with dev delay with/without dysmorphism
• Highly targeted approaches (FISH, gene sequencing) for specific syndromes where genotype-phenotype correlation is high. Although if NMD, sequential testing is expensive and time consuming.

Question 4

How does array CGH work

Answer 4

• Array consists of thousands of immobilized DNA fragments adhered to a surface.
• Test and reference DNA are labelled with different fluorescent dyes (Cy3 and Cy5), which hybridise competitively with probes in array.
• Ratio of Cy3 and Cy5 for each spot will indicate loss or gain of material in respective chromosomal region.

Question 5

Advantages of array CGH

Answer 5

• Higher resolution than karyotype
• Whole genome approach
• Little DNA needed so can be done on uncultured cells (faster processing)
• Analysis can be flexible. e.g. custom arrays or analysis of specific regions (parental testing) so less chance of incidental findings
• Data stored for easy reanalysis in future if needed

Question 6

Disadvantages of array CGH

Answer 6

• Cannot detect balanced rearrangements, triploidy, low level mosaicism and marker chromosomes.
• May miss aberrations depending on size and array coverage.

Question 7

What Consortium published in 2010 a statement supporting the use of array CGH as a frontline test in children with ID

Answer 7

International Standard of Cytogenomic array consortium

Question 8

Did the use of arrays increase detection rate in cohort of children with ID and other congenital anomalies

Answer 8

• Yes. To about 15-20%

- 3% with karyotype

Question 9

Databases available to aid interpretation of VUS

Answer 9

• DGV (database of genomic variants).

- DECIPHER (database of chromosomal imbalances and phenotypes in humans using ensemble resources)

Question 10

Why are follow up studies important

Answer 10

-To see if an imbalance is de novo or inherited.

Question 11

What is the DDD project

Answer 11

• Decipher Developmental Delay project
• Provides a catalogue of genetic changes linked to clinical features to aid clinicians to diagnose developmental disorders.
• Improve the understanding of the genetic aetiology of developmental disorders.
• 30,000 samples from 10,000 families (in 2014).