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Page 430                                       Ciolino et al. J Transl Genet Genom 2022;6:429-42  https://dx.doi.org/10.20517/jtgg.2022.15

               discussed by Hoang et al., genetic heterogeneity seems to be a common feature of clinical sequencing data.
               Thus, although a broad range of evidence has indicated an association between genes and ASD, variations in
                                                                           [1]
               gene expression and non-penetration are today accepted as widespread .

               Nowadays, many commercially available gene panels are offered. However, other risk factors have been
               associated with ASD aside from genetic susceptibility (such as prenatal diet and  prematurity) .
                                                                                                        [3]
               Microbiota-gut-brain axis alterations have also been implicated in neurodevelopmental disorders including
               ASD . From toddlers to aging adults, gastrointestinal (GI) issues, dysbiosis, oxidative stress, mitochondrial
                   [4]
               dysfunction, microglial activation, barrier permeability, and systemic alterations have been found in people
               diagnosed with ASD. As part of a new approach to thinking about the role of genetics in ASD, researchers
               are increasingly examining the causes of ASD in terms of degrees of risk and susceptibility, as opposed to
               deterministic factors. Furthermore, known genetic polymorphisms in individuals with ASD could be
               considered carriers of susceptibility, whereas genetic mutations might be more associated with risk. Because
               ASD is diagnosed according to behaviors, it is not possible to explore genetic risk during prenatal
               development. Today, brain development during the prenatal, neonatal, and postnatal stages of life, as well as
               the brain-body link at the systemic level during postnatal development, must be considered when
               formulating hypotheses about the etiology of ASD.


               Nowadays, gene lists from autism gene panels have been found to be insufficient for ASD diagnosis, as
                                      [5]
               further evidence is needed . As clearly discussed in a recent paper, if the application of a targeted gene
               panel to an affected individual’s genome is negative for pathogenic variation, one cannot conclude that a
                                             [6]
               contributive variant is not present . Under these circumstances, other factors should be considered in
               addition to genetics, such as selected metals, iodine, vitamins, folate, and biotin . Within the framework of
                                                                                  [7]
               epigenetics, brain-body homeostasis must be taken into consideration. Beyond genetics, epigenetics, and
               transcriptomics within and outside the brain, physiology and systems biology should be taken into account
               in understanding ASD.

               Given the complexity of ASD, as well as its heterogeneity, an overall approach must include environmental,
               nutritional, and immune as well as genetic factors. Consequently, ASD diagnoses based only on the results
               of commercial gene panels might have limited clinical accuracy, unless there is clear evidence of a genetic
               abnormality (e.g. suspected Fragile-X syndrome, FXS). This should be considered when developing
               procedures for primary screening, particularly in developing countries in which gene panel diagnoses might
               be cost-prohibitive for the majority of the population.


               Likewise, and especially considering those in developing countries with limited access to healthcare services,
               healthcare providers should assess the cost-benefit ratio of performing genetic tests when there is no
               syndromic phenotype for ASD. The main problem lies in the cost of genetic studies and the fact that the
               findings regarding non-pathogenic mutations do not offer a therapeutic perspective. Indeed, identifying a
               mutation outside a specific clinical context does not provide tools for treatment and can increase the costs
               for the family or medical services providers. It can also seriously affect the will of the family and the
               therapeutic and medical team regarding the opportunities for the patient. The detection of a mutation does
               not imply pathogeny or an automatic correlation with ASD. However, the concomitant medical problems
               (CMP) to ASD diagnosis have individual importance, and they should be correctly evaluated, diagnosed,
               and treated.


               The recent literature shows strong evidence of autoimmunity linked with ASD in individuals with FXS.
               Lisik et al. reported that a subgroup of FXS patients (43.48%) tested positive for serum anti-neuronal
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