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Clinical Geneticists Caution that Abnormal CMA Findings May Negatively Impact Adoption Process

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NEW YORK (GenomeWeb) – Higher-resolution chromosomal microarray analysis may provide a greater diagnostic yield than conventional techniques, but the ability of CMA to identify more variants of unknown or potentially pathogenic significance may be a double-edged sword when it comes to children in the adoption process.

Clinical geneticists at the West of Scotland Regional Genetics Service in Glasgow described the issue in a recent letter to the journal Archives of Disease in Childhood.

In the letter, the authors said they are aware of at least one case where an abnormal CMA finding prompted a prospective foster parent to withdraw from the adoption process, citing the array finding, even though the child, an 18-month-old boy, suffered from mild developmental delay, and the link between the finding and his phenotype was questionable.

"The child in question had experienced a turbulent prenatal period, which may have explained the delay, but the pediatrician ordered the array and then reported the abnormal finding back to the foster parent, who withdrew their request before the case was referred to us to discuss the finding," said lead author Mark Hamilton, now a special registrar in clinical genetics at Nottingham University Hospitals NHS Trust.

"I think most of my colleagues at other genetics centers who have read the letter have told me that they have experienced something similar," Hamilton told BioArray News this week. CMA "certainly has at least created more anxiety during the adoption process," he added.

Hamilton said that he was encouraged to write the letter to ADC after his experience working in Scotland, where there is a "particularly high rate of maternal substance abuse" and a correspondingly high proportion of so-called looked-after children, or LACs, a British legal term for children in public care. Given the incidence of developmental delay and behavioral problems associated with these LACs, Hamilton suspects that there are likely a significant number of LAC cases being referred to the West of Scotland Regional Genetics Service for CMA.

The data on how many LACs are referred for CMA, however, has been difficult to extract from social statistics. According to the letter, between Aug. 1, 2012, and July 31, 2013, 525 children in Glasgow and environs were newly subject to a care order from their local authority for reasons including neglect or abuse. Within the same period, the West of Scotland Regional Genetics Service received 262 requests for CMA from child development clinics in the same region.

Of these, just 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," the authors wrote in the letter. "Undoubtedly, there were more [LAC] cases coming through child development clinics," Hamilton noted.

Of the six LAC samples, four, or 67 percent, yielded abnormal results of indeterminate significance, and in all cases it was not possible to obtain parental samples to further investigate pathogenicity, the authors reported.

The crux of Hamilton and his fellow authors' argument therefore is that children at risk for certain phenotypes – developmental delay, for instance – given maternal substance abuse or unstable early childhoods are being referred for CMA, which then yields findings of unclear significance that may hurt them later in the adoption process.

"Developmental delay is overrepresented in [LAC], and children are in the adoption process often because of environmental factors," said Hamilton. "Our concern is that CMA would be seen as a baseline test," he said. Given these issues, Hamilton and co-authors are now urging pediatricians to "think twice about sending the sample and to consider the potential for stigmatization."

As noted in the paper, developmental delay among LAC is likely to be "multifactorial in origin," meaning that even if they do carry potentially pathogenic variants, environmental factors may play a major role in determining whether or not a pathological phenotype will manifest. Additionally, the authors cited research showing that a stable home environment provided by a foster parent can positively influence the behavioral development of LAC.

"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," the authors wrote. Instead, they argued that, in the absence of "red flags," such as dysmorphic features and 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."

"Autism spectrum disorders are clinical diagnoses," said Hamilton, noting that an array finding will represent genetic susceptibility to these disabilities rather than a real diagnosis. "We are not talking about changing a clinical test, but we are really talking about not putting isolated children who have perhaps mild developmental delay in the absence of other red flags at risk for stigmatization."

In addition to cautioning pediatricians and child development clinics about ordering CMA for LAC with mild developmental delay, Hamilton and his fellow authors believe there is a role for social services to play when it comes to communicating the results of CMA to potential adoptive parents.

"In the process of writing the article, we engaged with local adoption services, and they also said [CMA] was an issue, and that they had experienced issues in finding placement for children because of an abnormal finding," said Hamilton. "We are now visiting centers to see if we can teach them to better communicate the subtleties and limitations of findings, and to encourage similar dialogue within other centers," he said.

Hamilton and co-authors also aim to speak with social workers, to "help them feel more literate about these tests and give them more confidence in communicating the results."

And things are only going to get more complicated for all of the parties involved going forward.

In the paper, the authors noted not only the growing use of CMA, but also of exome and whole-genome sequencing in pediatric cases, where the risk of yielding "incidental or ambiguous results stands to become greater than ever." This trend is coupled with a growing interest among adoptive parents to use such technologies as part of the process. Some adoptive parents, for instance, are using consumer genomics services to obtain information about a child's ancestry, the authors wrote.

Given the inherent risks in using array and sequencing data as components of the adoption process, the authors suggested that further work is required to achieve a "rational basis for patient selection for these technologies."

In the letter, the authors suggested a number of areas for future research. These include the identification of clinical parameters that correlate with the probability of useful CMA results, and the evaluation of the contribution made by formal dysmorphic assessment by a clinical geneticist to diagnostic yield in such mild cases.

The authors also said there is a need to study the "longer-term psychosocial implications" of unclear genetic findings made in childhood, both in the context of adoption and among the general population, as to better inform policies for reporting results in the future.

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