Combined genetic tests could aid autism diagnosis

Scientists have found that two genetic analysis techniques can increase the number of causative mutations found in children with autism spectrum disorder (ASD).

The study, published in JAMA, also indicated that selecting children for genetic testing on the basis of clinical examination could help identify those who will benefit most from it.

Dr Stephen Scherer, from the Hospital for Sick Children in Toronto, Canada, and his team studied the DNA of 258 children with ASD using chromosomal microarray chip analysis (CMA), which looks for duplicated or missing segments of chromosomes.

Using this method, they found that 24 (9.3 percent) of children had a genetic mutation that could contribute towards the features of ASD.

The team also analysed the DNA of 95 randomly selected children and their parents for additional whole-exome sequencing (WES) analysis – a more extensive test that can detect single nucleotide mutations, which identified eight children (8.3 percent) as having a clinically relevant genetic mutation.

For those children where both the CMA and WES analysis had been used, the percentage of diagnoses improved to 15.8.

In addition to these genetic tests, each child also underwent a detailed physical evaluation and were categorised according to clinical morphology.

The researchers found that children with more physical anomalies (such as unusual measurements of the face, hands and feet or structural brain abnormalities) were more likely to receive a genetic diagnosis than those with fewer anomalies.

Using the combined CMA and WES testing, 36.7 percent of those with complex autism (defined as 6 or more physical anomalies) were diagnosed compared with just 6.3 percent of those with essential autism (three or fewer anomalies).

The findings from this study suggest that the rate of genetic diagnoses of ASD could be significantly improved if both CMA and WES were used as first-line genetic testing. However, Dr Scherer et al note that 'the use of WES is still largely within the research domain'.

'Our data suggest that medical evaluation of ASD children may help identify populations more likely to achieve a molecular diagnosis with genetic testing,' they add.

The authors conclude that that it is important for multiple genetic testing methods to be used in combination with detailed clinical histories and physical examinations to improve diagnosis.

Writing in an accompanying editorial, Dr Judith Miles from the University of Missouri in Columbia, agreed: 'It is incontrovertible that precise diagnoses pave the way to better medical care, improved surveillance, better functional outcomes and informed genetic counselling.'

She added that, in cases where genetic testing is harder to come by, such as for insurance or geographical reasons, clinical examination could help select a subset of children who have the highest chance of receiving a genetic diagnosis.

'It seems possible that it will not be too long before [there is a] recommendation to include whole-exome DNA sequencing as a first-tier ASD test, if not for all ASD diagnoses, certainly for children with physical dysmorphology,' Dr Miles concludes.