ReviewImplementation of genomic arrays in prenatal diagnosis: The Belgian approach to meet the challenges
Introduction
The implementation of genomic array in prenatal diagnosis reflects the potential of this technique to fulfil the longstanding need for a diagnostic test with a higher resolution and hence higher yield than conventional karyotyping. Indeed, the majority of foetuses with ultrasound (US) abnormalities have normal karyotypes, but numerous reports have demonstrated an increased detection of clinically significant, submicroscopic genomic imbalances with microarray in these high risk pregnancies. This higher yield is also apparent in pregnancies with lower risk such as increased maternal age or abnormal first trimester screening [Coppinger et al., 2009, Fiorentino et al., 2011, Lichtenbelt et al., 2011, Rooryck et al., 2013, Valduga et al., 2010, Wapner et al., 2012].
However, the introduction of array technology in a routine prenatal setting brought novel challenges. Both technical aspects of performing a genome-wide microarray - such as which type of platform and resolution should be used - and ethical issues are a subject of debate. The latter include the indications for prenatal array, the guidelines on how to deal with variants of unknown significance (VUS) and incidental findings, as well as how pre- and post-test counselling should be organised [Dondorp et al., 2012, Evangelidou et al., 2013, Vetro et al., 2012]. However, though these issues require proper handling and careful discussion, they should not lead us away from the primary goal, i.e. providing an improved prenatal genetic diagnosis.
Here, we report a national consensus guideline between the eight Centres for Medical Genetics in Belgium on the use of genomic array in prenatal diagnosis. We agreed on practical re-commendation on the organisation of pre- and post-counselling and how to interpret and report prenatal array results. These guidelines, which are subjected to constant evaluation and refinement, aim to be a practical aid for those routinely using prenatal arrays.
Section snippets
Pre-test counselling
As with every other genetic test, pre-test counselling of couples who are offered prenatal array remains of the utmost importance. Besides information on the purpose and restrictions of the test, parents can be informed about which results will be communicated to them and which will not. Also, certain difficult situations can be anticipated during the pre-test counselling, such as the issue of uncertainty because of VUS, variants associated with highly variable phenotypes or incidental
Technical aspects
Different genomic array platforms exist, with different resolutions and possibility to detect certain aberrations such as uniparental disomies or triploidies [Tyreman et al., 2009]. Table 1 summarizes the technical aspects of prenatal microarray diagnosis. The resolution should be a balanced decision between maximising the detection yield of the test and minimising the number of variants of unknown significance. Considering these aspects, we reached consensus to use 60k arrays (60,000 probes)
Reporting policy
- a.
Classification of variants
Our reporting policy is largely determined by the classification of the CNVs in three different categories, i.e. pathogenic, benign and unclassified variants (Fig. 1).
The knowledge on pathogenic CNVs or benign variants without functional consequences is usually based on prior knowledge. A number of criteria have been applied to evaluate the clinical significance of a certain CNV.
- 1.
Benign CNVs are variants that are repeatedly found in the normal population and are not
- 1.
Post-test counselling
In case of an abnormal result, parents are offered genetic counselling without unnecessary delay. During post-test counselling, two different characteristics of a CNV will need to be considered: the severity of the phenotype and the penetrance and variability of the disorder.
The severity of a condition depends on various factors including severity of intellectual disability, presence of malformations and opportunities for prevention or treatment. Prenatal genetic counsellors already have
Legal position and considerations of unreported data
The decision not to report certain variants implies that a distinction is made between the laboratory protocol and the final report. It also implies that data not communicated to the parents will also not be communicated to the physicians involved (neither the gynaecologist nor the clinical geneticist). However, since this information is retained in the laboratory, it is currently unclear whether this information is considered part of the medical file of the patient and hence if it can be
Conclusions
We present for the first time a national consensus approach on how counselling and interpretation of results are managed in Belgium when using microarray in prenatal diagnosis. This consensus was reached based on available literature data and the experience of the individual centres in several pilot studies. The establishment of a national Ad Hoc Committee has proven very useful: prior to initiating microarray in prenatal diagnosis, the Committee set out the recommendations on variant
References (31)
- et al.
Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity
Genet Med
(2010) Prenatal counseling and the detection of copy-number variants
Genet Med
(2013)- et al.
Women’s experiences receiving abnormal prenatal chromosomal microarray testing results
Genet Med
(2013) - et al.
Actionable, pathogenic incidental findings in 1000 participants’ exomes
Am J Hum Genet
(2013) - et al.
Microduplications at 22q11.21 are associated with non-syndromic classic bladder exstrophy
Eur J Med Genet
(2010) - et al.
22q11.2 Microduplication in two patients with bladder exstrophy and hearing impairment
Eur J Med Genet
(2010) - et al.
Recurrent reciprocal genomic rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy
Am J Hum Genet
(2007) - et al.
Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia
Am J Hum Genet
(2010) Microduplication 22q11.2: a new chromosomal syndrome
Eur J Med Genet
(2009)- et al.
Prenatal diagnosis using array-CGH: a French experience
Eur J Med Genet
(2013)
Estimates of penetrance for recurrent pathogenic copy-number variations
Genet Med
A copy number variation morbidity map of developmental delay
Nat Genet
Whole-genome microarray analysis in prenatal specimens identifies clinically significant chromosome alterations without increase in results of unclear significance compared to targeted microarray
Prenat Diagn
Anomalies of the TCF2 gene are the main cause of fetal bilateral hyperechogenic kidneys
J Am Soc Nephrol.
Arrays in postnatal and prenatal diagnosis: an exploration of the ethics of consent
Hum Mutat
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