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Ciolino et al. J Transl Genet Genom 2022;6:429-42 https://dx.doi.org/10.20517/jtgg.2022.15 Page 439

Ohashi et al. confirmed that only 10% of people with non-syndromic autism had findings of genes related to
[58]
[33]
ASD in the ES as well as other genetic reports . The authors were clear that the identification of gene
variants was not easy to interpret or apply in clinical practice.
CMP outside the brain and those related to known vulnerabilities in ASD should be evaluated, diagnosed,
and treated according to the protocols for syndromic and non-syndromic autism. Even in syndromic
[59]
autism (ASD with XFS or Down’s syndrome ), there are many CMP that should be diagnosed and
[60]
treated carefully.

Figure 3 shows the approach of the AIM and how the GM is included. The brain and body interact through
different pathways and mechanisms, and CMP outside the brain may influence neurological and psychiatric
CMP in people with ASD [47,48] . The findings of genetic testing should not be considered as confirmation that
a patient’s overall presentation is solely related to genetics, especially given the exhaustive clinical studies on
CMP that are needed. Finally, genetic testing (CMA, Exome sequencing (ES)-EWS) may be useful when
applied to syndromic autism, for both the patient and his/her parents and caregivers. It enables clarification
of the overall situation and often provides clues regarding other medical issues.

CONCLUSION
*Whereas the GM assumes a linear relationship between a behavior and the effect of genes from conception
to fetal prenatal brain development, the AIM of ASD takes a transdisciplinary approach in which the whole
body must be considered. The AIM considers not only genetics but also epigenetics and neurological,
psychiatric, pediatric medical, environmental, exposome, emotional, and social factors via a
bio-psychosocial perspective.

*Genetic tests should be considered as a part of a complex frame in which their contributions are
acknowledged for particular medical genetic issues (such as Cornelia de Lange, DiGeorge, and FXS). This is
especially the case in children with developmental issues since birth or the first months of life or those with
clear symptoms of chromosomic differences (Down’s syndrome) and an ASD diagnosis. In individuals with
a genetic syndrome, regression is sometimes found with the subsequent diagnosis of ASD. Genetic testing is
important in individuals with clear signo-symptomatology of genetic diseases or vulnerabilities with
different complexity/presentation and evolution (such as polymorphisms in the MTHFR gene or
mitochondrial disorders). Based on the response to treatments of CMP in people with ASD, anamnesis,
dysmorphisms, and trajectory, genetic testing focused on specific subgroups could provide clues regarding
pathogenesis and etiology.

*Regression (as loss of social abilities, speech and behavioral changes) is very well explained by epigenetic,
environmental, and neo-peri-post-natal exposure factors. The AIM considers the permeability of the
intestinal barrier and the BBB as components of the model. Because regression is observed in nearly 90% of
people with ASD, it is necessary to ratify the whole body vision of ASD and the concept of an underlying
systemic encephalopathy, where genes are a vulnerability risk and not a determining factor. An integrative
approach is needed in ASD, and the three-hit model and dynamic and static encephalopathies should be
considered.

*Responses to treatment(s) of CMP in individuals with ASD allow the identification of main groups and
subgroups of people diagnosed with ASD. A paradigmatic shift in research is urgently needed, where the
genetic vulnerabilities in these different subgroups are categorized by responses to CMP treatments. This
information could give clues regarding the pathogenesis and etiology of non-syndromic and syndromic