Deciphering the Prenatal Microarray Alan Ma O&G Meeting 12th 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 Karyotype 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 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 Higher yield Genome-wide Delineates deletions/ duplications more clearly – ‘what genes are in there?’ = more precise answer 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 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 Free to use Data-overload USCS Genome Browser http://genome.ucsc.edu/ Decipher Database https://decipher.sanger.ac.uk/index Free to use Data-overload Curated database of CNVs (Wellcome Sanger) Need membership (easy)

USCS Genome Browser

Type in Coordinates A deletion was detected on CGH microarray 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 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

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Links to OMIM