• Guidelines
• Microarray
• Clinical genetics
• Genome-wide
• Genetic screening/counselling

The University of Toronto's McLaughlin Centre invited medical genetics professionals and international advisors to consider the challenges in applying new genome-wide technologies to prenatal testing in Canadian genetics centres, and to set the stage for practice guidelines with the hope of national consensus. The gathering on 2 October 2014 included 59 clinical or laboratory geneticists, genetic counsellors and maternal-fetal medicine specialists, from 17 centres in eight provinces. Other speakers were ethicist Dr Kerry Bowman, and geneticists Drs Bettina Blaumeiser (Belgium) and Bronwyn Kerr (UK). Expository presentations were followed by break-out discussion groups.

Provincial jurisdiction over healthcare means interprovincial discrepancy in resources for genetics and related services, with access further stratified by geographical issues such as proximity to major centres. The Canadian College of Medical Geneticists (CCMG) and Canadian Association of Genetic Counsellors (CAGC) are national professional certifying bodies who, along with the Society of Obstetricians and Gynaecologists of Canada (SOGC), contribute policy and practice guidelines concerning genomic medicine, for consideration by individual provinces and centres. These practicing professionals recognise that early guidance can minimise regional disparities, although local influences and new technology development typically outpace policy. This one-day conference brought practitioners together from across the country to consider how to anticipate what is poised to be a dramatically different paradigm for prenatal testing.

Genomic (‘chromosomal’) microarrays have become the standard of care for many diagnostic issues in the postnatal realm, often replacing G-banded karyotypes. Prenatal application of genomic assays (microarrays and whole-exome or whole-genome sequencing) to fetal DNA from amniotic fluid or chorionic villus samples (CVS) (or perhaps eventually maternal circulation) comes with greater stakes and challenges. Considered in the context of other sources of information, what questions and concerns about the pregnancy are to be addressed? What combination of tests can most effectively and efficiently address those questions? Given other information, when is a genomic assay indicated? Will these assays eventually usurp other approaches to monitoring pregnancies?

Non-invasive prenatal testing (NIPT) is a screening strategy by which cell-free fetal DNA in maternal circulation is assayed for evidence of aneuploidy. Specific tests originally included common aneuploidies (trisomies 21, 18 and 13) but repertoires are expanding to include sex chromosome aneuploidies and certain microdeletion syndromes, albeit with higher associated false-positive rates and lower predictive value. As with other screening tests, any positive NIPT finding must be followed with a direct assay through one of the ‘invasive’ routes.

A multicentre UK study, Evaluation of Array Comparative genomic Hybridisation in prenatal diagnosis of fetal anomalies (‘EACH’), compared array outcomes with those from traditional G-band analysis in pregnancies with increased nuchal translucency (NT) or structural abnormality. Arrays indeed detected 50% more findings. The strong message was that uncertainty during pregnancy is toxic. Most centres employed an expert panel to consider whether to report various unclear findings.

The UK Joint Committee on Genomics in Medicine agreed, at a February 2014 workshop, that microarray should replace karyotype in the context of specific ultrasound findings (increased NT or structural abnormality). They considered issues that would eventually apply to NIPT and whole-exome or whole-genome sequencing during pregnancy, establishing working groups to prepare guidance on the issues.

In Belgium, the eight genetics centres came to consensus about procedures for prenatal microarray, including reporting guidelines overseen by an ad hoc committee. A national database for findings is in progress.

In the USA, analysis by chromosomal microarray has become the standard of care for invasive prenatal testing. A large study (Wapner et al N Engl J Med 2012;367:2175–84) compared chromosomal microarray with karyotype for routine prenatal diagnosis in >4000 samples, concluding that microarrays identified additional clinically relevant cytogenetic information, missing only balanced rearrangements and triploidies. The American College of Obstetricians and Gynecologists therefore recommended (2013) prenatal microarray for women of any age with abnormal ultrasound findings, and for analysis of fetal demise or stillbirth, emphasising the need for pre- and post-test counselling and documentation of informed consent, particularly regarding findings of uncertain significance. A statement by the American College of Medical Genetics and Genomics addressed NIPT screening for trisomies 13, 18 and 21, anticipating eventual whole fetal genome sequencing. They commented that more comprehensive testing by amniocentesis or CVS are recommended when fetal abnormalities are detected, and to confirm all positive screen results.

Montreal's Hôpital Ste. Justine had 5 years of laboratory experience with the first 1000 prenatal genomic microarrays, most following detection of fetal abnormalities on ultrasound. About 10% yielded pathogenic results, including some that were undetectable by G-banded karyotype. Their reporting protocol reflects a more conservative approach to disclosing variants of unknown significance (VOUS) for prenatal than for postnatal tests. The consent form specifies what will and will not be reported, and offers some choice about disclosure. Strong guidelines for reporting were advocated.

Experience with processing of about 4000 postnatal diagnostic cases per year at SickKids Hospital was shared, followed by discussion about whether reporting criteria should be different in the prenatal scenario. Among cases referred postnatally for developmental delay or multiple congenital anomalies, with thresholds of 500 kb for duplications and 200 kb for deletions, labs at SickKids and Credit Valley Hospital found 15% to have VOUS. This outcome will evolve as knowledge bases improve. More conservative reporting thresholds for prenatal cases could mean different results reported for the same original data.

A counselling perspective came from experience with new prenatal technologies at Toronto's Mount Sinai Hospital. Uncertainty is far from a new dilemma in prenatal genetics, and counsellors can draw on experience to manage new situations. Tests need to be aligned to the questions, with balance between diagnostic advantages and ambiguity. Services such as NIPT, whether publicly funded or purchased privately, will create need for follow-up (ie, by karyotype or microarray) by the public healthcare system. These should not be undertaken without the ability to offer necessary supports, with an ever greater counselling role.

Before the conference, registrants were surveyed with questions around testing availability and access, uncertainty, choice and consent. There was relative consensus among these Canadian practitioners that (1) they would benefit from national guidelines, (2) a consent form is needed, (3) women should be offered some choice with respect to the nature of information to be delivered or withheld and (4) NOT all women should be offered invasive prenatal testing. There was evidence of a shift in thinking towards expanding the use of microarray.

Over the next 5–10 years, prenatal medicine will be influenced by progressive policy changes adapting to transformative technologies. Biochemical screening may give way to first trimester NIPT for all pregnancies as costs decrease. A transition through prenatal testing by microarray and exome sequencing will eventually be replaced with fetal whole-genome sequencing. The conference presented important data for the professional bodies to use in drafting guidelines for the Canadian landscape.