Definition of Autism and Autism Spectrum Disorders (ASD)
Autism is a neurodevelopmental disease, characterized by early childhood-onset impairments in communication and social interaction alongside restricted and repetitive behaviors and interests.
In 2013, according to the criteria from the 5th version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), the American Psychiatric Association has re-classified autism under the official umbrella term ‘autism spectrum disorder’ (ASD), along with Asperger disorder, childhood disintegrative disorder, Rett disorder and pervasive developmental disorder not otherwise specified (PDD-NOS), in order to allow clinicians to account for the variations in symptoms and behaviors from person to person.
An alternative term for ASD is ‘autism spectrum conditions’, that is used to avoid the perceived negativity associated with the word ‘disorder’. The term ‘autism’ may now be generically used as a synonym of ASD.
Patients affected by ASD can show inflexible interest, insistence of sameness in environment or routine, repetitive motor and sensory behaviours (like flapping arms or rocking), increased or decreased reactions to sensory stimuli. As severity of the symptoms is widely variable, the disorder is not always easily to be recognized. Associated comorbid phenotypes may include intellectual disability, epilepsy, soft neurologic motor signs, gastrointestinal and cardiac problems.
Mendelian diseases with ASD vs isolated autism
Over 100 rare Mendelian diseases have been associated with ASD, such as fragile X syndrome, Rett syndrome, tuberous sclerosis, or Timothy syndrome. In these diseases, autism represents just a part of the clinical spectrum of complex condition, which are clearly genetically determined and show well know dominant, recessive, or X-linked transmission. In some cases, these syndromes recognize even a chromosomal origin.
However, pure, isolated autism is a multifactorial condition. It is thought that genetic factors, alongside with environmental factors, may result in susceptibility to the condition. So, isolated autism is etiopathogenically different from Mendelian disease associated with ASD, where the cause is clearly monogenic or chromosomal. The etiopathogenically puzzling condition of isolated autism shows actually a recurrence in sibs which is lower than traditional genetic disorders. In fact, the risk to sibs is just 5% (and rapidly decrease for consanguineous relatives of the parents of a child with isolated autism).
Genetic studies on large numbers of ASD patients have identified several hundreds of possible susceptibility genes, however no clear formula to precisely assess the risk in sibs and other relatives has been discovered, the aforementioned empyrical risk of 5% given for sibs remains the most used.
Whole exome sequencing studies in ASD
To provide you with complete information, we’d like to report some interesting evidences arosen from whole exome sequencing studies on ASD patient, although we insist in highlighting that ASD is not purely genetic:
• a significant number of ASD risk genes and chromosomal regions are related to the production of proteins involved in synaptic structure/function and the modification of chromatin,. Other genes are related to proteins expressed in fetal brain, transcription factors and RNA binding proteins, and targets of the Fragile X Mental Retardation protein.
• Rare inherited variants have a smaller average effect size and reduced penetrance compared to de novo pathogenic mutations. Data on whole exomes from trios established a key role for de novo germline mutations in autism (de novo mutations in protein-coding genes and in non-coding regions contribute to risk in about 30% of simplex autism cases).
• Loss-of-function (LoF) or likely-gene-disrupting (LGD) mutations are more likely to be associated to ASD risk when they are identified in brain-expressed genes that are under strong evolutionary constraints and which are intolerant to LGD variants.
Overall, it is tempting to state that SNVs in risk genes and specific CNVs underlie the majority of ASD cases, but this is not the case. ASD exome analyses have just opened a new era of more comprehensive molecular investigations.
Havdahl et al. Genetic contributions to autism spectrum disorder. Psychol Med. 2021 Oct; 51(13):2260-2273. PMID: 33634770
Ramaswami et Geschwind. Genetics of autism spectrum disorder. Handb Clin Neurol. 2018; 147:321-329. PMID: 29325621
Manoli et State. Autism Spectrum Disorder Genetics and the Search for Pathological Mechanisms. Am J Psychiatry. 2021 Jan; 178(1):30-38. PMID: 33384012
Official Site of American Psychiatric Association (APA): https://www.psychiatry.org/
Harper PS, Practical Genetic Counselling (6th edition) – Arnold.
omim.org at large
Genereviews at large (https://www.ncbi.nlm.nih.gov/books/NBK1116/?term=)