Published: 02-09-2015 08:15 | Updated: 02-09-2015 10:02

Children with ASD should receive a molecular diagnosis

Children with autism spectrum disorder should be given more thorough medical examinations and genetic tests that cover the entire genome as soon as possible after their clinical diagnosis. This will facilitate more exact molecular diagnoses, which can inform families about biological causes of the disorder and help the children obtain better care. This according to a paper by Swedish and Canadian researchers published in the scientific journal JAMA.

Autism spectrum disorder (ASD) is an umbrella term for different types of autism of varying degrees of severity, of which all are considered neuropsychiatric functional impairments and are characterised by social communication and interaction difficulties as well as limited interests and stereotypical behaviour.

It has long been known that co-morbidity with ASD is high: over 70 per cent of all children with the disorder have one or more other psychiatric or medical diagnoses. A group of Swedish and Canadian researchers now claim that children with ASD should routinely be offered early genetic analyses – chromosomal microarray and whole-exome sequencing – to make a molecular diagnosis by identifying the genetic abnormality causing the functional impairment.

Abnormalities in specific genes

The present study involved 258 Canadian children given ASD diagnoses between 2008 and 2013. By only examining the children medicinally or by means of a medical examination combined with a search for abnormalities in specific genes, the team was able to make a molecular diagnosis for one in twenty children. However, when they conducted broader genetic analyses, this number increased.

The researchers employed two different methods, chromosomal microarray and a more recent technique called whole-exome sequencing, which can analyse the entire genome. Using these methods, the team was able to give almost 16 per cent of the children an exact molecular diagnosis. None of the children had the same genetic disorder, demonstrating the complexity and heterogeneous nature of the factors underlying ASD.

“Our data suggests that children with ASD should be offered a genetic examination that covers the entire genome,” says the paper’s lead author Kristiina Tammimies, researcher at the Department of Women's and Children's Health, and affiliated to the Center of Neurodevelopmental Disorders at Karolinska Institutet (KIND). “For families, it can be important to understand the biological reason for the disorder and get guidance of possible increased risk for same disorder in younger siblings. We also know that certain genetic anomalies behind ASD are associated with conditions like obesity or diabetes, so the more we learn the more we will be able to provide care at an individual level.”

Whole-exome sequencing techniques

About 20 per cent of the 258 children had more than five minor physical abnormalities, such as a single palmar crease, uncommonly low-set ears and/or congenital deformities (e.g. heart defects). In this subgroup of children, the researchers were able, using both chromosomal microarray and whole-exome sequencing techniques, to identify a molecular diagnosis in 40 per cent of the children.

“If there is a need to prioritise which children should receive these two genetic diagnostic tests, it would the children with more complex clinical symptoms, by which I mean those who have these physical abnormalities or congenital defects in addition to ASD,” says Dr Tammimies. “As in this group we had the best success on making a molecular diagnosis.”

The project was financed with grants from several bodies, including the Swedish Research Council, and was conducted with researchers from the Memorial University of Newfoundland and SickKids Hospital in Toronto, Canada.


Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children with Autism Spectrum Disorder
Kristiina Tammimies, Christian R. Marshall, Susan Walker, Gaganjot Kaur, Bhooma Thiruvahindrapuram, Anath C. Lionel, Ryan K. C. Yuen, Mohammed Uddin, Wendy Roberts, Rosanna Weksberg, Marc Woodbury-Smith, Lonnie Zwaigenbaum, Evdokia Anagnostou, Zhuozhi Wang, John Wei, Jennifer L. Howe, Matthew J. Gazzelone, Lynette Lau, Wilson W. L. Sung, Kathy Whitten, Cathy Vardy, Victoria Crosbie, Brian Tsang, Lia D’Abate, Wai Tong, Sandra Luscombe, Tyna Doyle, Melissa T. Carter, Peter Sztarmari, Susan Stuckless, Daniele Merico, Dimitri Stavropoulos, Stephen W. Scherer and Bridget A. Fernandez
JAMA, online September 1, 2015