Download A deletion was detected on CGH microarray. The ISCN (2009)

Deciphering the
Prenatal Microarray
Alan Ma
O&G Meeting
12th November 2014
Aims
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Role of microarray in prenatal testing
How we decipher the microarray results
Common scenarios
Unrelated/incidental findings of significance
Future directions
Standard G-banded karyotype
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Pickup ~ 3% in congenital abnormalities (MCA)/intellectual disability (ID)
Good for translocations, aneuploidy, large deletions and duplications
Resolution around 5-10Mb
Rapid turnaround 36 hours (QFPCR aneuploidy) to 1 week (full culture)
There are…
• 20 000 nuclear genes/genome
• 5000 OMIM-listed with known
disease-related phenotypes
• 15 000 uncertain/experimental
phenotypes
Chromosomal Microarray
Chromosomal Microarray
CMA vs karyotype
Array
• Pickup additional 4-6% above G-banded
karyotype in prenatal setting of structural
abnormality on ultrasound
• 15% in MCA/ID postnatally
• Detects microduplications and deletions
not seen on conventional karyotype
• Resolution 10-400kb
• Hi-res arrays can pick up single gene CNVs
• Will also pick VOUS in 2-4% of cases
Karyotype
• Pickup 3-4%
• Resolution 5-10Mb
• Will pickup balanced
translocations and
structural
rearrangements
60K Agilent Array
Can you spot the deletion?
Can you spot the deletion?
Can you spot the deletion?
Normal copy of 9
Deleted copy of 9
Array: reported as 7.3Mb deletion in 9q22
Benefits and disadvantages
Benefits
• Higher yield
• Genome-wide
• Delineates deletions/
duplications more
clearly – ‘what genes
are in there?’ = more
precise answer
Disadvantages
• Cannot detect balanced translocations
or map imbalances
• Misses point mutations and small
del/dups < 10kb
• Can ‘unmask’ carriers of recessive
conditions, unrelated conditions and
consanguinuity!
• Can be hard to interpret results and
counsel - VOUSes
• Turnaround time
• 2 weeks
• Longer if issues with DNA
quality/quantity, parental studies
Neonatal consult
• Respiratory distress
• Nasal piriform aperture stenosis
• Hypoteloric and hypotonic
RESULT:
A deletion was detected on CGH microarray.
The ISCN (2009) description is:
arr 18p11.32p11.31(138,963-6,963,069)x1
CONCLUSION:
Microarray testing detects a terminal deletion, within chromosome 18
bands p11.32 to p11.31. This has minimum size 6.82Mb, and extends
from position 0.14 to 6.96Mb. (Max.size is 7.08Mb, from 0 to 7.08).
The deletion includes approx. 40 known genes, from ROCK1P1 to
LAMA1. Two of these are associated with OMIM-listed disease, namely
LPIN2 & TGIF1.
2 ways to analyse this
USCS Genome Browser
http://genome.ucsc.edu/
• Free to use
• Data-overload
Decipher Database
https://decipher.sanger.ac.uk/index
• Curated database of
CNVs (Wellcome Sanger)
• Need membership (easy)
USCS Genome Browser
Type in Coordinates
A deletion was detected on CGH microarray.TheISCN (2009) description is:arr
18p11.32p11.31(138,963-6,963,069)x1
Type in Coordinates
A deletion was detected on CGH microarray.TheISCN (2009) description is:arr
18p11.32p11.31(138,963-6,963,069)x1
You can customise
Decipher is easier
Links to OMIM