VIEWPOINT ARTICLE

Developing standards for chromosomal microarray testing counselling inpaediatricsEmma Godfrey (ecg910@bham.ac.uk)1, Phillipa Clark2

1.School of Medicine and Surgery, University of Birmingham, Birmingham, UK2.Developmental Paediatrics, Starship Children’s Health, Auckland, New Zealand

KeywordsChromosomal microarray, Counselling,Developmental disorders, Genetic testing,Guidelines

CorrespondenceE Godfrey, School of Medicine and Surgery,University of Birmingham, B15 2TT Birmingham, UK.Tel: +0121 414 3771 |Fax: +44 (0)121 414 3971 |Email: ecg910@bham.ac.uk

Received2 December 2013; accepted 11 February 2014.

DOI:10.1111/apa.12601

ABSTRACTChromosomal microarray testing (CMA) generally aids paediatric genetic diagnosis.

However, pre-CMA counselling is important as results can be ambiguous, generate

uncertainty and raise ethical issues. We developed standards for counselling and giving

families results; using these we evaluated practice for children seen by the Auckland

Developmental Paediatric team in 2011. Pretest discussion was documented in 14 of 28

subjects and potential outcomes in 4of 28. 8 of 28 received information leaflets, 1 of 28

gave signed consent. 3 of 3 with abnormal results and 4 of 5 with variants of unknown

significance (VOUS) were offered clinical genetics referral. 8 of 20 families with normal

results were written to; two with abnormal results were informed face-to-face and one in

writing; most VOUS were communicated by phone, voicemail or letter.

Conclusion: CMA testing requires clear patient information sheets and in-depth pretest

discussion for informed consent, timely feedback of results and genetics referral as

appropriate. Authoritative guidelines and training are needed to strengthen CMA

counselling.

INTRODUCTIONCurrent guidance recommends that all children withdevelopmental disabilities receive first-line cytogenetictesting in the form of chromosomal microarray (CMA)(1). This compares thousands of DNA sequences from apatient sample against a control DNA sample, identifyingcopy number variants (CNVs), low level mosaicism andchromosomal rearrangements (2). Aiding diagnosis ofchildren suffering from developmental disabilities, it detectsabnormalities in 15–20% of those with developmental

delay, intellectual disability and multiple congenitalabnormalities, and in 5–10% of those with autistic spectrumdisorder (2).

Compared with conventional karyotyping, genomic test-ing interrogates regions of the genome outside knowndisease causing genes and can detect unexpected changes inmultiple regions. Although this can benefit patients byincreasing the possibility of reaching a diagnosis, there areconcerns that CMA is more likely to give uncertain orunexplained results (3–5). CNVs for example are present in>1% of the population, with the majority being benign (6).The relatively novel nature of the test means databases arelimited, making it difficult differentiating between benignand pathogenic variants, resulting in the term “variants ofunknown significance” (VOUS) (2). International databas-es help determine the likely significance of VOUS, but

Abbreviations

CMA, Chromosomal microarray; CNV, Copy number variant;DNA, Deoxyribonucleic acid; VOUS, Variant of unknownsignificance.

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parental genetic testing is often required; new mutations areprobably causal, but this is less likely if the VOUS is presentin parental DNA (3). Interpretation is further complicatedby the multifactorial nature of many disorders, togetherwith variable expressivity, multiple phenotypes andincomplete penetrance (7). This increased uncertainty cancreate patient anxiety and professional doubt (7). Moreover,CMA does not detect balanced translocations, inversions,transpositions or small-scale or point mutations, as it onlyon has a maximum resolution of 1 kb; therefore, a normalresult does not mean there is no genetic cause (2,3).Although time-consuming, the complexities of CMA needto be explained to families as even when ‘normal’ there isstill an increased likelihood of having another child withsimilar problems and further targeted testing may be needed(2). Families should also be forewarned that CMA couldpotentially uncover incidental findings (e.g. concomitantpresymptomatic mutations and issues relating to paternity)(1–3,5,8).

In many settings, consent is required obtained to storeDNA (9); and it is important to be aware that there is greatvariability in cultural beliefs worldwide; this is particularlypertinent in New Zealand (under Rights 7.9 and 7.10 of theHealth and Disability Commission Code), in respect forMaori culture(10). The tangata whenua (people of the land)view DNA and genes as tanonga (property/possessions); in1840, chiefs signed the Treaty of Waitangi with the Crownto have ‘undisputed control over their land, their villagesand their possessions’; therefore, some Maori do notsupport patenting of genes or sending DNA off-shore fortesting and storage (10).

As CMA results can be ambiguous, generate uncertaintyand raise ethical issues families should have careful pre-and post-test counselling to achieve informed consent andreduce anxiety (1,3) Information sheets should supplementconsultations, reminding families what has been discussed,helping decrease anxiety and obtain informed consent(1,2). It is recommended that abnormal results or VOUSshould be discussed face-to-face as this increases under-standing and minimises confusion from misleading internetsearches. Subsequently a clinical genetics referral is useful,allowing specialists to explain what the findings mean andthen monitor for new advances.

Currently, despite several papers stressing the need forformal guidelines, no such guidelines covering CMA coun-selling have been published by any professional body, withthe American Academy of Pediatrics recommendations forgenetic testing predating CMA use (1,8,11). The Develop-mental Paediatrics Team at Auckland hospital were awareof differing practices between doctors, with possible short-comings in service provision. We therefore developed draftstandards for counselling and evaluated them, with the aimof developing guidelines to improve the experience offamilies. These standards were based on current literatureand professional opinion; we hypothesised that thesecounselling guidelines were not fully followed in practice.No similar evaluations of clinical practice have previouslybeen published.

METHODSDraft standards for counselling (Table 1) were developedusing the current literature (US, New Zealand, Australianand European articles) and through discussions withgenetic and developmental paediatric specialists.

We conducted a retrospective review of medical recordsfor children who had CMA requested by the tertiary referralAuckland Developmental Paediatric team over a 1-yearperiod (2011, n = 28). One patient was excluded as theywere on intensive care while tested. The medical recordswere examined for concordance with the draft standards forcounselling developed above.

Approval for the study was granted after the AucklandDistrict Health Board confirmed with the regional ethicscommittee that according to their guidelines no specificethics application to the committee was needed.

RESULTSPretest discussion was documented in 14 of 28, potentialoutcomes in 4 of 28 and DNA storage in 3 of 28. Eightreceived information leaflets and one gave signed consent.All three with abnormal results and 4 of 5 with VOUS wereoffered clinical genetics referral. 20 had normal results, fiveVOUS and three had abnormal findings. 8 of 20 familieswith normal results were written to. Two with abnormalresults were told their results in clinic and one was writtento. VOUS were either communicated face-to-face (1), overthe phone (2), by voicemail (1) or by letter (1).

Table 1 Standards for evaluation of clinical practice in relation to counselling forchromosomal microarray testing in children with developmental disorders inAuckland, New Zealand

The following should be taken and documented

Pretest:

1. All families should have appropriate pretest counselling in order

to achieve informed consent(1–4,7,10,11,15–19) including

discussion of potential test out comes(1,7,8,15–18) and of storage

of DNA (10)

2. A plan should be made on how results will be communicated,

including normal results and VOUS (7,19)

3. All families should be given a CMA Information sheet

(1,2,7,15,16,19,20)

4. All should sign a consent form agreeing to the procedure (1)

Test results: unless agreed otherwise in advance and so documented

5. Families should be informed of their abnormal test result

face-to-face, within 4 weeks of the result becoming available (7,19)

6. Families should be informed of VOUS within 4 weeks of the result

results becoming available, how this is done being decided in result

advance with the patient (7)

7. Families should be informed of normal results in writing within

4 weeks of the results becoming available (2,7)

8. A genetics referral should be offered to all families where there was

result an abnormal or VOUS result within 4 weeks of the result

result becoming available (2,7,16,17,20)

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Godfrey and Clark Chromosomal microarray testing counselling

DISCUSSIONThis study showed that clinical practice varied greatly, withmanagement of no cases meeting all the recommendedguidelines. The only standard achieved >50% of the timewas genetics referral. Although this could reflect lack ofdocumentation of discussion, this review points to anunmet need for authoritative guidelines from professionalbodies to improve clinical practice.

While development of authoritative guidelines specific tomodern genomic testing will assist health professionals inproviding effective counselling for families, there are otherbarriers to implementation of such counselling (4). CMAwas introduced in Auckland in 2010, meaning that thisaudit reflects a time where clinicians were becomingfamiliar with this relatively new test. Although the clinicalteam are now confident in using CMA, when it wasintroduced many said they were uncertain. Several articlesworldwide have drawn attention to need for better trainingof those ordering CMA as many feel unequipped tocounsel and interpret results (1,7). This is a particularissue in many settings as the capacity of the medicalgenetics workforce is often insufficient to meet demand,and training in clinical genetics for general and subspe-cialty paediatricians is often limited. Time pressures in theclinical setting will impact on how counselling is given,and capacity issues may make it challenging to arrangeconsultations with families within the recommended four-week period to discuss abnormal findings or VOUS. Forwhole genome sequencing, estimates of the face-to-facetime required for the informed consent process range ashigh as 6 h (12) together with up to 5 h of patient contactfor delivery of results (13).

Discussion following this evaluation of CMA testingrevealed general agreement that the standards developedwere appropriate for future use, with the possible exceptionof written consent. It could be argued that CMA does notcause ‘significant adverse effects on the consumer’ andtherefore may be unnecessary (9). Contrastingly, Cohenet al. have argued that patients found it served legally todocument consent and as source of information for thefamily.(I) Auckland’s genetics department supported thisview. Therefore, it was decided to use consent forms atclinicians’ discretion.

With the rapidly expanding field of clinical genetics andthe introduction of exome and whole genome sequencing,development of authoritative guidelines in this area is evenmore imperative as such high resolution testing detectsmore incidental findings and VOUS (1,2). The proportionof VOUS in this study was towards the upper end of the5–20% reported in the literature, but this should not beover-interpreted given our small sample size and the rapidlyevolving nature of arrays and the databases and algorithmsused to interpret these (14). This study has highlighted theneed to proactively develop guidelines and implementclinical education in relation to CMA. This would improvethe experience of families undergoing genetic testing.Several papers have stressed the need for formal guidelines,

but no guidelines covering CMA counselling have yet beenpublished by any professional body.

ACKNOWLEDGEMENTSThis work was supported by generous awards from TheClinical Genetics Society, The Stuart Green MemorialTrust, and The Institute of Medical Ethics. We would liketo thank Peter Reid, Statistician at the Auckland DistrictHealth Board Research Office, for help with data collectionform design and for data analysis.

FINANCIAL DISCLOSURENone.

COMPETING INTERESTSWe declare that we have no conflict of interests.

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