Deciphering thePrenatal Microarray

Alan MaO&G Meeting12th November 2014

Aims• 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• 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 thisUSCS Genome Browser

http://genome.ucsc.edu/

• Free to use• Data-overload

Decipher Databasehttps://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.The ISCN (2009) description is:arr 18p11.32p11.31(138,963-6,963,069)x1

Type in Coordinates A deletion was detected on CGH microarray.The ISCN (2009) description is:arr 18p11.32p11.31(138,963-6,963,069)x1

You can customise

Decipher is easier

Links to OMIM