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Page 434 Ciolino et al. J Transl Genet Genom 2022;6:429-42 https://dx.doi.org/10.20517/jtgg.2022.15

Kreiman and Boles assessed five children with ASD and genetic mutations in whom genetic testing
[32]
provoked certain therapeutic actions and finally an improvement in well-being . In three of the five cases
(TNF-Receptor Associated Protein 1 gene [TRAP1], choline acetyltransferase [CHAT], and Solute Carrier
Family 6 Member 8 [SLC6A8] mutations in 3 different patients), important positive changes in the
ASD-related symptoms were reported when adequate medical treatments were applied. Other examples are
the use of ketoglutarate for reducing pain and fatigue in a patient with a glutaminase 2 (GLS2) mutation,
and the use of melatonin for sleep disturbance in a child with an AANAT mutation. AANAT is a gene that
encodes aralkylamine N-acetyltransferase, which is a key regulator of circadian rhythms.

Despite the many genetic syndromes described, alterations in the chromosome microarray (CMA) may
only occur in 9%-10% of people with ASD, whereas that in the whole genome, such as in Exome whole
sequencing (EWS), may only occur in up to 21% of people with ASD. Indeed, a positive correlation does not
imply causation, but merely a contribution, which may be shared with other contributors.

Stafford et al. examined several cases of genetic syndromes characterized by the specific and acute
presentation of symptoms and/or dysmorphisms, in which genetic confirmation was necessary to determine
[33]
appropriate medical interventions . For these medical genetic issues, genetic testing is undoubtedly
warranted. However, instead of recommending genetic testing only for this subgroup, the Genetic Model
proposes genetic testing for all people diagnosed with ASD. This approach might be prohibitive, especially
for low-income countries.

In a systematic review and meta-analyses from 2015, estimates of ASD range from 11% for 22q11.2 deletion
[34]
syndrome to 61% in females with RTT . For all syndromes, odds ratios showed that people with ASD have
a higher risk of genetic abnormalities than the general population. Several studies have examined the
overlapping genetic traits in individuals with epilepsy/seizures and ASD and in those with psychiatric
diagnoses and ASD . Frye et al. examined the biological abnormalities shared by ASD and epilepsy, and
[35]
found abnormalities in minicolumn architecture and GABA neurotransmission . Medical abnormalities
[36]
associated with both ASD and epilepsy include genetic syndromes, metabolic disorders, mineral and
vitamin alterations, heavy metal bioaccumulation, and immune dysfunction . Treatment-resistant epilepsy
[36]
was more prevalent in children diagnosed with ASD (i.e., they had a mitochondrial dysfunction or disorder
[37]
and alterations in cerebral folate transport) compared with those without an ASD diagnosis .
[38]
Recently, the heterogeneity of ASD was confirmed in a large study by Kuo et al. . However, genetic ASD
research continues as if the role of genes in ASD is causal and not contributive . Indeed, MTHFR C667T is
[39]
the only variant that has been found to indicate genetic vulnerability for ASD diagnosis. More than 1000
genes involved in ASD were reported by Doi et al., who suggested that ASD is a neurodevelopmental
[40]
disorder (NDD) related not only to genetic but also environmental factors . This approach is distinct from
that in previous manuscripts about genes and ASD. A new framework and research avenues are needed to
increase the quality of life of individuals diagnosed with ASD. Multiple studies about CMP in people with
ASD have supported the need for new models [26,41-44] , especially considering the high rate of early death in
[45]
people with ASD among other important topics. Finally, a complete review indicated that the evidence
[42]
accumulated during the last 20 years (but mainly the last 5 years) demonstrates that the genetic
commonalities among individuals with ASD are only associations and have no direct causation link, i.e.,
they are related to ASD risk and vulnerability but are not deterministic.

HOW THE ENVIRONMENT AFFECTS VULNERABLE NEWBORNS: THE ROLE OF CMP IN
TODDLERS AND INFANTS WITH ASD