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Page 436 Ciolino et al. J Transl Genet Genom 2022;6:429-42 https://dx.doi.org/10.20517/jtgg.2022.15

Scheme 1. Different approaches in the Genetic Model (GM) and Advanced Integrative Model (AIM) with respect to CMP, biomarkers,
and genetic testing.

THE ROLE OF GENES AND GENETIC TESTING IN THE AIM FOR ASD
The GM, as presented in Figure 1, relates behavior to the effect of genes from conception to fetal prenatal
brain development in a deterministic manner. Even when epigenetics are considered, the focus of the field is
largely the prenatal life and the brain. In this model, the body, the system biology, and the postnatal
development of the whole body are not discussed. The CMP outside the brain in people with ASD are
dismissed as irrelevant with respect to the ASD core symptoms, and may also be considered compensation
effects related to the effect of genetic vulnerability. Many previous studies have demonstrated the need to
profoundly revise this application of the GM. The push to continue in this line of research has generated
profound divisions among the parents of people diagnosed with more severe ASD, and high need of
support, and people diagnosed with presentations of ASD that require less support.

The focus on genes as causation in ASD could diminish the value of genetic testing for those cases where it
is useful and even life-changing (i.e. mitochondrial disorders). Active research regarding the biomarkers of
ASD is focused on genetic findings, brain mechanisms [54,55] , and proteomics . The final goal is to detect
[56]
subgroups in people diagnosed with ASD using biomarkers, and to use this information to guide treatment.

Although this research has some important aspects, there are other approaches and mechanisms that are
related to the integration of genetics-epigenetics and the effect of the exposome on whole-body function,
which are centered on the CMP found in different ASD studies. For instance, a recent manuscript presented
a mechanism for the generation of ASD considering the whole body, the gut-brain axis, and the brain and
gut permeabilities .
[57]
Our previous manuscript presented a way to group individuals with ASD according to the individual
responses to treatments for CMP . Three main groups can be identified depending on the response
[26]
(positive or null) to treatments for CMP. The first group overcomes the ASD diagnosis following the
treatment of CMP, the second group exhibits changes in ASD symptoms, i.e., a reduction in support needs
in response to the treatment of CMP, and the third group shows no changes in ASD symptoms.