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The value of chromosomal microarray analysis (CMA) in identifying causative copy number variants in children affected by developmental delay is well described, most recently by the excellent review from Srour and Shevell1 in this journal. As with many novel diagnostic technologies however, the power of CMA to make biological observations in unprecedented detail also carries the possibility of revealing findings whose clinical significance is not fully understood, such as variants of variable expressivity or incomplete penetrance. The potential for such findings to carry stigma should not be overlooked.2
Between 1 August 2012 and 31 July 2013, 525 children in Greater Glasgow were newly subject to a care order from their local authority for reasons including neglect or abuse.3 Against a backdrop of high maternal substance abuse, such ‘looked after children’ (LAC) are often placed with relatives, foster carers or in residential units, and many subsequently come to medical attention with developmental delay. Within the same period, our service received 262 requests for CMA analysis from child development clinics in Greater Glasgow. Six were specifically received from the Looked After and Accommodated Children's Service although the true prevalence of LAC in this cohort is likely to be higher. Of these six samples, four (67%) yielded abnormal results of indeterminate significance, and in all cases it was not possible to obtain parental samples to further investigate pathogenicity.
As many LAC ultimately undergo adoption, the reporting of ambiguous genetic data can have far-reaching implications. We have experience of an 18-month-old boy in foster care, investigated for mild speech and motor delay. He was found to carry a microduplication at 15q11.2 between break points 1 and 2, a recognised susceptibility variant for behavioural difficulties and autism with incomplete penetrance.4 ,5 The child showed no evidence of social disability, but before the result could be discussed in the genetics clinic, a prospective adopter withdrew their application citing the finding of a chromosomal abnormality as their primary reason.
The critical role of a nurturing home environment in optimising outcomes for children at risk of behavioural problems, such as those affected by fetal alcohol spectrum disorders (FASDs), is well recognised.6 Although enrichment of developmental delay among LAC is likely to be multifactorial in origin, even in the presence of inherited susceptibility it is probable that environmental factors play a major role in determining whether a pathological phenotype will manifest. As such, reporting data of limited clinical utility but which might adversely influence prospects of adoption may in fact result in poorer outcomes for this group.
We therefore consider that for children with mild developmental delay, in the absence of ‘red flags’ such as dysmorphic features or congenital malformations, there is a role for observation before electing to embark upon genetic investigation, particularly where adverse environmental factors offer a plausible alternative explanation.
Clinical suspicion of FASD however presents a challenging scenario in light of the recognised phenotypic overlap of FASD with chromosomal disorders.7 Involvement of a clinical geneticist in the diagnostic process for this group, enabling detailed assessment of the available family and perinatal history as well as careful examination for subtle dysmorphic features may be useful to evaluate the utility of proceeding to genetic investigation, a step which is supported by British Medical Association (BMA) guidelines.8
In all cases where CMA is undertaken in a child subject to a care order, effective communication of the prognostic limitations of a result to the relevant colleagues in Social Services and to prospective adopters is undoubtedly of paramount importance.
As the diagnostic use of genomic technologies such as exome sequencing and whole genome sequencing moves towards routine practice, the potential for non-targeted genetic investigation to yield incidental or ambiguous results stands to become greater than ever. Recent data from the USA demonstrate interest among adoptive parents in the power of such technology to fill gaps in knowledge regarding their child's inherited risk of disease as well as ancestry, with some having already used direct-to-consumer genetic services to seek information relating to the latter.9 The appetite for disclosure of genomic data in the preadoption context has not been assessed, but is likely to be encountered to some extent.
Therefore in consideration of the potential for detrimental effects of data arising from CMA, exome sequencing and whole genome sequencing, we suggest that further work is required to achieve a rational basis for patient selection for these technologies. Useful areas of further research would include identification of clinical parameters which correlate with probability of clinically useful results, as well as evaluation of the contribution made by formal dysmorphic assessment by a clinical geneticist to diagnostic yield in mild or non-specific cases. Furthermore, improved insights are required into the longer term psychosocial implications of ambiguous genetic findings made in childhood, in the context of adoption and among the general population, in order to better inform policy relating to reporting and disclosure of results.
This communication was based on discussions with the late Dr John Lorimer Tolmie, whose gentle good humour and dedication to his most vulnerable patients continue to inspire those privileged to work with him.
Contributors The observations described in this communication were first made by JLT. MJH, SJ, NM and NMS contributed to developing the concept. NMS reviewed the background literature. SJ and NM produced the quoted data relating to the West of Scotland Genetics Service. MJH wrote the communication and subsequent revision in discussion with NM and SJ.
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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