The origins of autism spectrum disorders

Autism spectrum disorders (ASD) are characterized by learning and social integration difficulties. This major communication disorder can take various forms and is not necessarily associated with an intellectual disability. It affects about 700,000 people in France.

There is more and more evidence that ASD has genetic origins. However, diagnosis and treatment of ASD does not progress at the same rate.

For 20 years and in 26 day hospitals and mental health facilities in the Greater Paris region (1), Prof. Arnold Munnich, a pediatrician and geneticist at Necker-Enfants malades hospital AP-HP, a professor at the University of Paris, and the president of the Imagine Foundation, has conducted a study aimed at finding the genetic causes of ASD. This falls within the scope of the Élan Retrouvé Foundation’s Genetic Regional Mobile Consultations, which are led by psychiatrist Moïse Assouline. With the aide of a mobile team of geneticists and nurses from Imagine Institute, Inserm/University of Paris/AP-HP, and the Élan Retrouvé Foundation, Arnold Munnich has met with 502 patients with ASD and their relatives, in their places of care or homes.

Teams have noted that in many cases, no consultation or genetic test had been offered to patients.

Results which confirm the need to extend genetic analyses to a greater number of patients

Patients were offered various genetic tests. The Comparative Genomic Hybridization on DNA Network (array CGH)—which has replaced karyotyping as it is more successful—was carried out on 388 out of the 502 patients. It helped to detect genetic abnormalities in 34 of them. In 19 patients, there were non-hereditary abnormalities, in 4 others the abnormalities were inherited from one of the parents, and for the remaining 11 inheritance could not be established (adopted child, patient deceased, etc.).

In the 141 patients for whom the CGH had not detected anything, New Generation Sequencing (NGS) helped to identify genomic variants linked to ASD and intellectual disabilities for 33 patients. 23 of these variants were not hereditary. The remaining 10 had been passed on by the parents, and half of these variants were linked to the X chromosome.

In addition, screening for Fragile X Syndrome—a rare genetic syndrome often causing cognitive impairment—was carried out in 312 patients who had never been previously tested for this syndrome; 4 of them tested positive for this syndrome.

In total, 27 of the disease’s mutated genes were detected. Every case of ASD diagnosed presented as a moderate to severe intellectual disability. Results show that combining the NGS technique with CGH and fragile X syndrome screening helped to significantly improve diagnostic accuracy.

For a better diagnosis of autism spectrum disorders

This study led Prof. Arnold Munnich and his colleagues to offer all children with ASD a diagnostic strategy based on initially studying the most common genes found in patients with ASD with intellectual disability. Most often, the genetic alterations involved in ASD are not hereditary. In this study, mutations are de novo in 23/33 cases, i.e. 70% of cases. In this case, the genetic diagnosis helped to remove any doubt relating to the risk of passing it on to another child. It also helped to inform the parents wanting to have a second child of the risks.

Although recognizing the genetic origins of ASD has not yet resulted in a treatment, it is a significant step forward for parents for whom, according to Prof. Arnold Munnich, “knowing the mechanisms involved in their child’s disease is not seen as a stigma, but rather as a relief, because it helps them to better understand and even to overcome difficulties.” And to clarify “naming the disease is the first step in treating it, it opens up the possibility of surmounting the disease through thought, it is treating the symptoms, sometimes with medication, sometimes with adapted educational or re-educational methods, sometimes with better care.”

In addition, genetic diagnosis paves the way for a better understanding of the various mechanisms of ASD and for research that may lead to new therapeutic strategies.