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Page 432 Ciolino et al. J Transl Genet Genom 2022;6:429-42 https://dx.doi.org/10.20517/jtgg.2022.15

Major neuropsychiatric conditions that are behaviorally defined using the Diagnostic and Statistical Manual
of Mental disorders (DSM) criteria have strong convergence with well-known neurological conditions (e.g.,
ataxias and Parkinson’s disease), but less overlap with non-neurological conditions. Psychiatric diagnoses
affect both tissues involved in the central control and peripheral (heart and muscle-skeletal) nervous
systems. The results of Torres emphasize the importance of considering both the brain-body connection
[17]
and the contributions of the peripheral nervous systems to mental health . These relationships are not
taken into account in the classic approach of gene causation in ASD, even when the complexity has been
demonstrated to be huge. CMP outside the brain (cited above), neurological issues (epilepsy/convulsions,
sleep issues, movement disorders) and psychiatric diagnoses co-occur many times in the same person with
the ASD diagnosis. A recent manuscript in the field of pediatrics (2022) cited a known problem in genetic
studies, that is, that heritability estimates are primarily derived in such a way that they may overrate the role
of genes. Moreover, in most cases, gene-only (G) and genetic (G)* shared environmental influences (E)
[18]
(cited as GxE) are considered to be genetic . GxE involves the interaction between the genotype and the
environment. The problem of identifying genetic contributions and neglecting the possibility that genes act
in concert with environmental agents is a general one, and occurs even in recent studies. Indeed, Volk et al.
stated that it “is highly likely that the interplay of gene variants and environmental factors contributes to a
substantial proportion of autism” . A systematic review reported wide-ranging heterogeneity in the
[18]
prevalence of co-occurrent medical problems with ASD. They found that participants with ASD also had
attention deficit hyperactivity disorder (ADHD; to 86.00%), anxiety (up to 82.20%), depressive disorders (up
to 74.80%), epilepsy (2.80%-77.50%), intellectual disability (ID; up to 91.70%), sleep disorders
(2.08%-72.50%), sight/hearing impairment/loss (0.00%-14.90%/0.00%-4.90%), and GI syndromes (up to
67.80%). The high variation was associated with the heterogeneity and individual presentation of ASD . In
[19]
2022, a systematic review about GI symptoms in individuals with ASD reported a causal relationship
between changes in the gut-immune-brain pathway and ASD symptoms. In the review, GI symptoms were
correlated with eight themes: developmental regression, language and communication, ASD severity,
challenging behavior, comorbid psychopathology, sleep problems, and sensory issues . A recent study with
[20]
a monozygotic co-twin design with 224 twins (mean age = 17.70 years, SD = 6.28) indicated a correlation
between exposure to perinatal and postnatal risks and subsequent neurodevelopmental conditions. Their
[21]
results suggested that ASD might be linked with environmental risks early in life .

In a systematic review from 2021, Wei et al. reported that more than 200 susceptibility genes had been
[22]
correlated with autism . For almost every chromosome, cytogenic abnormalities have been reported.
According to the authors, candidate genes related to ASD might exist in nearly every chromosome .
[22]
However, these findings, along with those of other epigenetic studies at the brain level only, do not consider
how translational actions can improve the quality of life and outcomes in people with ASD. Indeed, the
influence of outside-the-brain factors deserves more attention, even though genes and genetic pathways
may be essential in unraveling the pathogenesis of ASD from a mechanistic point of view. For instance, in a
study of 1031 genes, David et al. reported that only 262 were directly associated with ASD, whereas the
others were related to other comorbid disorders . Furthermore, Díaz-Beltran et al. used a two-fold system
[23]
biology approach to propose a multi-comorbidity subtype of ASD . Finally, Klein et al. used a topic
[24]
modeling approach and concluded that a better understanding of the underlying pathogenetic mechanisms
involved in medical issues co-occurring with ASD may have clinical implications in the comprehensive
assessment and management of these patients .
[25]
Advanced Integrative Model
The Advanced Integrative Model (AIM) considers the ASD diagnosis as the name of an emerging
symptomatology. The underlying condition at the brain level may be thought of as a chronic, dynamic, and
systemic form of encephalopathy, a priori with respect to an ASD diagnosis, which is potentially