Born in the USA

Born in the USA

The American Approach to Prenatal Microarrays Primary Influences  ACOG recommendations, 2007, 2013  Wapner NEJM paper, 2012  ACMG recommendations...

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The American Approach to Prenatal Microarrays

Primary Influences  ACOG recommendations, 2007, 2013  Wapner NEJM paper, 2012  ACMG recommendations for NIPT, 2013  Secondary Influences 

 Insurance  Improvement in public databases and software analysis

tools  Laboratories experience with postnatal ▪ Private databases of local populations

  

Early amniocentesis (<15wks) should not be performed Amniocentesis and CVS safe (0.33-0.2% loss rate) Offer invasive testing if:  Previous fetus or child with an autosomal trisomy or sex

chromosome abnormality,  Current pregnancy with one major or at least two minor fetal structural defects identified by ultrasonography,  Either parent with a chromosomal translocation or chromosomal inversion, or parental aneuploidy.

Make available to all women to rule out aneuploidy, irrespective of a priori risk  CMA not ready for prime time – G-banding remains gold standard 

Obstet Gynecol. 2007; 110 (6):1459-67



Clinically significant CNV Detection rates  In presence of fetal anomalies, +6% DR  In otherwise normal pregnancies, +1.7%



VUS detection (all microarray)  3.4% total  1.8% Likely benign  1.6% Likely pathogenic



Misses (predictably)  Triploidies  Balanced rearrangements

N Engl J Med. 2012;367:2175-84



Use CMA

 For fetuses with abnormal ultrasound findings  For women of any age, because the anomalies

detected do not correlate to maternal age; but standard karyotype OK for otherwise normal pregnancy.  To analyze genetic material in cases of fetal demise or stillbirth.  Not to evaluate first- and second-trimester pregnancy loss.

 Require pretest and post-test genetic counseling  Informed consent  Documented

 Must include discussion of findings of uncertain significance, consanguinity, non-paternity, and adult-onset disease. Obstet Gynecol. 2012; 122 (6):1374-77



Generally, ACMG statement is guarded regarding the use of NIPT

 50% of cytogenetic abnormalities detectable by

amniocentesis or CVS will not be detected if only 13, 18 and 21 are screened  In the presence of fetal anomalies, invasive testing with CMA may be the better testing option  NIPT positive results must be confirmed by invasive testing  Recommendation for registry of PPV and NPV for clinically relevant metrics

Genet Med. 2013:15(5):395–398



Clinical utility of NIPT in the era of Prenatal CMA  Suited to pregnancies at increased risk for common aneuploidies based upon biochemical markers  Leads to more acceptance by patients  Fetuses with structural anomalies  If NIPT is normal, what is the post-NIPT residual risk for a chromosome abnormality that would be detectable by IT- CMA?  If NIPT is abnormal but not confirmed by IT- QFPCR or karyotyping, where does CMA fit in?



Public Databases  CNV databases: ISCA, DGV – curation is improving on an

ongoing basis 

Software  Array platforms come with vastly improved client

databases and analysis tools 

Expanded knowledge base – Postnatal array labs with Private Databases  Thousands of CNVs detected, categorized privately ▪ Rare, recurrent, benign variants for local population, and platform specific/design associated variation



Availability of Medical Insurance 

Not universal, despite 2013 practice guidelines from ACOG

 United Healthcare considers CMA medically

necessary for women undergoing invasive testing ▪ Effective June 1, 2014

 Capital Blue considers prenatal CMA still

investigational ▪ Effective date June 1, 2014



SNP or Oligo/SNP hybrid platforms  SNP data is primarily intended for detection of UPD in

imprinted chromosomes  Otherwise, minimum reportable AOH size is 15-25Mb and minimum reportable IBD is 4% 

Functional resolution is similar irrespective of platform used:~50Kb  Reportable VUS size is the same between platforms ▪ 1-1.5Mb loss ▪ 1-2Mb gain



Karyotyping is usually an ‘extra’



CMA with invasive testing has become a standard of care in the USA, BUT  Private insurance is inconsistent



Reporting standards are similar, irrespective of platform used  ISCA gene targets plus backbone  SNP or Oligo + SNP hybrid  Avoidance of reporting VUS <1Mb in size  Informed consent is required



NIPT  Recommended for aneuploidy screening  Not to replace CMA invasive testing when ultrasound anomalies are

present

1. 2.

3.

Lab platform comparisons Integrated algorithm (from screen to invasive testing) from ARUP National Reference Laboratory NIPT versus Invasive testing comparison

Comparisons

Labcorp

Baylor

Gene Dx

ARUP

Platform

2.6million/SNP

180K Oligo/SNP Combo

180K Oligo/SNP Combo (also a low res alternative)

2.6million/SNP

Minimal Targets

ISCA +

ISCA+

ISCA+

ISCA+

Test requirements

20cc fluid or 20mg villi or 3xT25+4slides

20-25cc fluid or 3035mg villi

20cc fluid or 2xT25 cultured cells (AF or CVS)

15-20cc fluid or 1015mg villi or 2xT25 flasks ,

VUS – deletions

>1Mb

>1Mb

1.5Mb

>1Mb

VUS -Duplications

>2Mb

>1Mb

1.5Mb

>2Mb

Claiming to report

50Kb

No info

500bp-100Kb

50Kb

UPD/Consanguinity Yes – no additional info available

UPD of imprinted chromosomes only

>4% of genome or >25Mb within a chromosome

>10% of genome or >15Mb within a chromosomes

Susceptibility genes

Yes – if clear phenotype known

No info

No info

No info

Karyotyping

Choice – extra

Always

Choice - extra

Choice – extra

Appendix 1.

Appendix 2. Algorithm from ARUP labs

Appendix 2. Algorithm from ARUP labs

BEFORE NIPT (2011) 

638 screen positive patients

WITH NIPT (2012-2013) 

398 screen positive patients

 47.2% underwent IT

 39.2% underwent IT

 52.8% declined further

 39.4% had NIPT

testing

 21.1% declined further testing

Net result of introduction of NIPT: More follow-up to screen positives but less invasive testing

Appendix 3. Prenat Diagn. 2013 Jun;33(6):542-6.