G C A T

T A C G
G C A T
genes
Review
The Autism Spectrum: Behavioral, Psychiatric and
Genetic Associations
Ann Genovese and Merlin G. Butler *

Department of Psychiatry and Behavioral Sciences, University of Kansas Medical Center, 3901 Rainbow Blvd.,
MS 4015, Kansas City, KS 66160, USA; agenovese@[Link]
* Correspondence: mbutler4@[Link]; Tel.: +1-(913)-588-1800; Fax: +1-(913)-588-1305

Abstract: Autism spectrum disorder (ASD) consists of a group of heterogeneous genetic neurobe-
havioral disorders associated with developmental impairments in social communication skills and
stereotypic, rigid or repetitive behaviors. We review common behavioral, psychiatric and genetic
associations related to ASD. Autism affects about 2% of children with 4:1 male-to-female ratio and a
heritability estimate between 70 and 90%. The etiology of ASD involves a complex interplay between
inheritance and environmental factors influenced by epigenetics. Over 800 genes and dozens of
genetic syndromes are associated with ASD. Novel gene–protein interactions with pathway and
molecular function analyses have identified at least three functional pathways including chromatin
modeling, Wnt, Notch and other signaling pathways and metabolic disturbances involving neuronal
growth and dendritic spine profiles. An estimated 50% of individuals with ASD are diagnosed with
chromosome deletions or duplications (e.g., 15q11.2, BP1-BP2, 16p11.2 and 15q13.3), identified syn-
dromes (e.g., Williams, Phelan-McDermid and Shprintzen velocardiofacial) or single gene disorders.
Behavioral and psychiatric conditions in autism impacted by genetics influence clinical evaluations,
counseling, diagnoses, therapeutic interventions and treatment approaches. Pharmacogenetics testing
is now possible to help guide the selection of psychotropic medications to treat challenging behaviors
or co-occurring psychiatric conditions commonly seen in ASD. In this review of the autism spectrum
disorder, behavioral, psychiatric and genetic observations and associations relevant to the evaluation
and treatment of individuals with ASD are discussed.

Keywords: autism spectrum disorder; behavior; genetic defects and associations; medical conditions;
Citation: Genovese, A.; Butler, M.G. pharmacogenetics; psychiatry
The Autism Spectrum: Behavioral,
Psychiatric and Genetic Associations.
Genes 2023, 14, 677. [Link]
10.3390/genes14030677
1. Introduction
Academic Editor: M. E. Suzanne Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with on-
Lewis set in infancy or early childhood, in which genetic and non-genetic influences acting either
Received: 2 February 2023
alone or in combination contribute to the development of ASD. According to the World
Revised: 3 March 2023 Health Organization, ASD is characterized by impairments in social and communication
Accepted: 6 March 2023 skills, rigid or repetitive behaviors, atypical interests and differences in the perception of
Published: 9 March 2023 sensory stimuli [1]. The neurodiversity paradigm diverges from the traditional medical
model’s understanding of autism as a disorder, viewing common traits in autism as neuro-
logical differences instead of deficits, thus shifting attention away from a disease model,
while highlighting unique autistic strengths and embracing autism as a manifestation of
Copyright: © 2023 by the authors.
neurological diversity that needs no cure [2].
Licensee MDPI, Basel, Switzerland.
Behavioral and psychiatric disorders in individuals with ASD are prevalent, and
This article is an open access article
their impact is significant. A growing body of research reveals evidence of the frequent
distributed under the terms and
association between ASD and irritability, aggression, self-injurious behaviors, ADHD,
conditions of the Creative Commons
anxiety, obsessive compulsive disorder, gender dysphoria, mood disorders, suicidality,
Attribution (CC BY) license (https://
substance use disorders, catatonia, psychosis and schizophrenia spectrum disorders. The
[Link]/licenses/by/
4.0/).
symptoms associated with many behavioral and psychiatric disorders that commonly occur

Genes 2023, 14, 677. [Link] [Link]

Genes 2023, 14, 677 2 of 21

in individuals with ASD can overlap with core characteristics of ASD, which results in
diagnostic challenges [3].
The risk for co-occurring behavioral and psychiatric disorders is influenced by indi-
vidual differences including age, intellectual functioning, sex and genetic factors [4], with
a majority of existing studies focusing on children and adolescents with ASD [5]. It has
been shown that older autistic adults are at lower risk for having a co-occurring psychiatric
diagnosis compared to their younger cohorts, a pattern similar to that found in the general
population [6]. There is even less that is known about co-occurring conditions in autistic in-
dividuals with intellectual developmental disabilities. Although about one-third of people
historically diagnosed with ASD have an intellectual disability [7], this subgroup is often
excluded in the literature describing behavioral and psychiatric disorders in ASD [8].
ASD is a heterogenous genetic disorder with a 4:1 male-to-female ratio and over 800
ASD-related genes recognized with hundreds of chromosome aberrations, dozens of identi-
fied syndromes and a complex interplay between inheritance and environmental factors
influenced by epigenetics [9–11]. Advances in understanding the role of genetics in human
disease, particularly disorders of neurodevelopment, have been achieved by revolutionary
changes in genomic technology with next-generation sequencing (NGS), computer program
analysis and bioinformatics. This knowledge has created the opportunity for more detailed
and rapid clinical evaluations and genetic testing options for patients presenting with
neurodevelopmental disorders, intellectual disabilities and ASD. The ability to provide
early diagnoses of inherited disorders has resulted in the development of clinical trials
leading to new treatments for up to 3% of the world’s population with developmental
disabilities, for whom there exist substantial comorbidities, high lifetime costs and the
associated emotional burden of living with conditions that were previously considered to be
untreatable [12–16]. The objective of this review is to demonstrate that advanced genomic
and pharmacogenetic testing has the potential to improve both diagnostic evaluations and
treatment interventions for individuals with autism.

2. Behavioral and Psychiatric Observations in Autism

2.1. Behavioral and Psychiatric Conditions Often Associated with Autism
2.1.1. Irritability, Aggression and Self-Injurious Behaviors
Autistic individuals often experience elevated levels of irritability (e.g., temper tantrums,
frustration or angry outbursts) and problem behaviors (e.g., physical aggression toward oth-
ers, self-injurious behaviors or property destruction). Deficits in emotional self-regulation
(e.g., using maladaptive emotion regulation strategies such as perseveration or shutting
down) are common in autism and may result in anger being experienced more intensively,
and in turn, strong negative emotions can trigger aggressive behaviors. Additionally,
impairments in social cognition including inaccurate assessments or misinterpretation of
social intent can promote aggressive behaviors [17].
Self-injurious behaviors (SIBs) are acts of physical harm inflicted upon oneself that
have the potential to result in injury. Examples include hitting, pinching, scratching, biting,
head banging and hair pulling. In contrast, stereotyped self-stimulatory behaviors typi-
cally involve repetitive or ritualistic movements, gestures, or vocalizations (e.g., repeated
sounds, words or phrases) [18]. These behaviors can be persistent or episodic, spontaneous
or repetitive, often without any identified cause, or may tend to occur within specific
contexts or in response to certain triggers or situations. Risk factors for more serious and
persistent SIBs include intellectual disability, limited communication skills, lower adaptive
functioning, impairments in impulse control [19], sensory processing deficits or chronic
sleep problems [20].

2.1.2. ADHD and Executive Functioning Deficits

Attention Deficit Hyperactivity Disorder (ADHD) is characterized as a neurodevel-
opmental disorder manifested by core symptoms of distractibility and impulsivity, either
with or without hyperactivity. In comparison to typically developing peers, limitations of
Genes 2023, 14, 677 3 of 21

executive functioning are common in both ASD and ADHD, suggesting that both may be
conceptualized through an “executive functioning deficit model” [21]. Executive functions
are cognitive control mechanisms that modulate perceptual experiences, motor responses,
emotion regulation and behavioral reactions, as well as enable cognitive skills providing the
ability to sequence, prioritize, plan, make decisions, anticipate novel situations, evaluate
risks, utilize effective problem solving and develop adaptive coping strategies [22].
Developmentally appropriate social skills are commonly underdeveloped or impaired
in both ASD and ADHD. The evaluation of social functioning involves an assessment of the
individual’s social skills within the context of a particular interpersonal encounter. Social
skills deficits in ADHD typically include a lack of attention to or disregard of situational
or non-verbal cues, as well as intrusive or impulsive tendencies in communication and
social interactions. In comparison, ASD related social challenges tend to manifest as either
poorly developed or awkward social skills, with an apparent indifference to or lack of
awareness for social cues, and for some individuals, this includes active avoidance of social
engagement [23].

2.1.3. Anxiety and Anxiety Disorders

Anxiety involves the expectation of a future threat, whether it is real or imagined.
Anxiety disorders differ from what is considered to be age-related normal anxiety or fear as
they cause significant distress, are functionally impairing, are excessive for the situation, or
persist beyond developmentally appropriate periods. Leo Kanner [24], in 1943, described
excessive anxiety in autistic individuals around unanticipated changes in the environment,
alterations in schedules or unexpected events, viewing the behaviors of an autistic child as
driven by an intense desire for maintaining sameness. His view was that difficulties with
adapting occur in response to obsessive, restricted and perseverative features associated
with autism. Rigid behaviors, including verbal rituals, compulsive routines (e.g., ordering
and lining up objects), restrictive or rule-based preferences (e.g., eating only foods of one
color), if interfered with or prevented, tend to trigger anxious distress.
Among the anxiety disorders associated with ASD, the most common ones are specific
phobias and generalized anxiety disorder, followed by social anxiety disorder and sepa-
ration anxiety disorder [25]. It can be clinically challenging to diagnose specific anxiety
disorders in the context of ASD due to shared features associated with both autism and
anxiety disorders. For example, social anxiety disorder which is characterized principally
by a fear of negative evaluation by others, and therefore, often leads to a lack of active
engagement in social situations, which can manifest similarly to the core social commu-
nication deficit seen in autism [26]. Children with ASD often experience emotional and
behavioral difficulties when they are overwhelmed with sensory stimulation. Deep pres-
sure is a therapeutic modality utilized in occupational therapy to have a calming effect
on the child by decreasing sympathetic arousal. An inflatable wrap called an autism hug
machine portable seat has been shown to reduce neurobiological stress as measured by
the sympathetic response, which in turn reduces problematic behaviors in children with
ASD [27,28].

2.1.4. Repetitive Behaviors versus Obsessive Compulsive Disorder

According to the Diagnostic and Statistical Manual of Mental Disorders, fifth ed. (DSM-
5), the symptoms associated with ASD include restricted, repetitive patterns of behavior,
interests or activities [29]. Repetitive behaviors in ASD can include recurrent vocalizations
such as repeating certain noises, words or phrases, fixating on topics of special interest, rigid
behaviors such as inflexible insistence on specific routines in everyday life, listening to the
same song or watching the same videos repeatedly, or ritualistic stereotyped movements
such as symmetric flapping or twirling of the hands, rocking of the body or the spinning of
objects. Repetitive behaviors characteristic of ASD may appear to be very similar to the
compulsive rituals often associated with obsessive compulsive disorder (OCD) [30].
Genes 2023, 14, 677 4 of 21

OCD is characterized by a pattern of obsessive thoughts and compulsive behaviors

that interfere with daily activities and cause significant distress. Obsessions in OCD consists
of intrusive thoughts, either driven by an intense need for organization or symmetry, in
response to fear of disease or contamination, or as an attempt to ward off unwanted urges
or morally unacceptable thoughts or images that trigger significant anxiety. Compulsive be-
haviors in OCD are typically performed in response to intrusive thoughts in an unconscious
effort to relieve distress. In comparison to OCD, repetitive behaviors in ASD are generally
preferred, performed for the purpose of self-soothing, and do not typically cause distress.
Repetitive behaviors in both OCD and ASD are often disruptive or time consuming and
can lead to behavior problems including tantrums or aggression, particularly when others
attempt to alter or interrupt the behavior [31].

2.1.5. Gender Dysphoria

Gender dysphoria is caused by a misalignment between a person’s biological or birth-
assigned sex and their personal experience of gender identity, whereas gender variance (or
gender diversity) describes when an individual’s gender role and behaviors deviate from
the culturally defined or socially expected gender norms [32]. Autistic individuals report
a higher number of gender dysphoric traits compared to that of non-autistic peers [33].
Multiple studies report that ASD is over-represented in those with gender dysphoria and
in gender-affirming specialty care clinics [34,35]. Strang et al. published clinical guidelines
to help guide evaluation and treatment considerations for adolescents with co-occurring
gender dysphoria and ASD [36].
Gender-diverse autistic adolescents and adults are known to have increased rates of
mental health problems, including elevated risks for depression and suicidality compared
to those of either autistic or transgender persons individually [37]. Due to associated
social and communication differences associated with autism, they can face significant
challenges in advocating for their gender-related healthcare needs. To optimize the success
in patient outcomes, it is essential that medical providers become familiar with established
standards of care for gender-diverse autistic individuals, help them to enlist family and
social support, provide guidance in accessing gender-affirming healthcare, actively partner
with other members of the patient’s care team to coordinate treatment interventions and
obtain effective mental health consultation when it is needed [38].

2.1.6. Depression and Bipolar Disorders

Major depressive disorder (MDD) consists of a predominantly depressed or irritable
mood, accompanied by a loss of interest or pleasure in previously enjoyed activities, as
well as a host of other distressing psychological and somatic symptoms, lasting for a period
of at least 2 weeks [29]. An approximately two-fold risk for developing major depression in
autistic young adults was reported in a population-based cohort study, which also found
that MDD is more common in those with ASD than it is in their non-autistic siblings. ASD,
particularly ASD without intellectual disability, is associated with elevated rates of major
depression in young adulthood, and it is likely that the explanation is related to both shared
genetic and environmental factors [39]. Identifying a major depression when it occurs in
the context of ASD can be challenging given the overlap of common depression symptoms
and features of ASD, as well as by a lack of evidence supporting the validity of commonly
used assessment instruments for diagnosing MDD in autistic individuals [40].
Bipolar Affective Disorder (BAD) has two main subtypes. Bipolar I Disorder, which
closely aligns with the classically described manic-depressive illness, involves both full-
blown manic and major depressive episodes, and if the patient is not stabilized with
effective treatment, it tends to evolve into a pattern of recurrent episodes that have the
potential to escalate, with an associated risk for brief periods of psychosis. Bipolar II
Disorder tends to follow a less severe course, defined by one or more episodes of major
depression and hypomania [29]. BAD is more likely to occur in association with autism
than it is in the general population. Not only is the risk of bipolar disorder greater for those
Genes 2023, 14, 677 5 of 21

with ASD compared to age- and sex-matched controls from the general population, but
the risk is also higher in family members with ASD than it is in non-autistic siblings [41].
Diagnostic challenges exist because when BAD occurs in the context of autism, it may have
an atypical presentation, thus causing either a lack of recognition or worse, an incorrect
diagnosis, given that when psychotic symptoms are present, the clinical picture can be
easily mistaken for schizophrenia [42].

2.1.7. Suicidality
The elevated risk for suicidality in ASD has been historically under-recognized. The
majority of studies evaluating suicidality in ASD have been conducted only in recent
years [43]. A landmark study that assessed suicidality in a sizable clinic population of autis-
tic adults formerly diagnosed with Asperger syndrome (an outdated diagnosis defining a
sub-group of individuals with ASD with normal intelligence and greater impairment in
social skills compared to those with other autistic traits) found that about two-thirds of
them endorsed a history of suicidal ideation, with one-third having previously planned
or attempted suicide [44]. Similarly, a population study in Sweden found that individuals
diagnosed with ASD were significantly more likely to have suicide listed as the cause
of death compared to the average proportion of suicide deaths reported in the general
population [45].
The stress associated with “camouflaging” (a term used to describe those with ASD
who intentionally mask their autistic traits or adapt their behavior with the goal conforming
to neurotypical expectations) in autistic adolescents and adults contributes to increased
stress, depression and suicidal behaviors in ASD [46]. Additional risk factors for suicidality
in ASD include a history of behavioral problems, bullying, victimization, male gender,
minority identity and lower socioeconomic status or educational attainment. Finally, the
associated risks for suicidal thoughts and behaviors shared with the general population
include recurrent self-injurious behaviors, psychiatric disorders and unstable employment,
all of which occur at a greater frequency for individuals with ASD [47].

2.1.8. Substance Use Disorders

An emerging body of research suggests that ASD is associated with double the risk
for developing a substance use disorder (SUD). There is no clinical evidence explaining the
lack of attention to the risk for SUD in ASD. The fact that SUDs were historically thought
to be rare among individuals with ASD may be understood in considering the divergent
culturally constructed narratives for the two conditions. The albeit naïve or simplistic ASD
narrative portrays the individual as blameless and innocent, whereas the judgmental and
moralistic narrative of SUD depicts the person as corrupt and unworthy, with the opposing
narratives leading to cognitive discordance, and hence, bias. Clinicians need to remain
vigilant when adopting the routine practice of screening individuals with ASD for SUD in
the same manner they would for other patients and provide appropriate treatment for this
common and potentially life-threatening co-occurring morbidity [48].
With regard to the susceptibility for developing SUDs, autistic individuals share
common risk factors that exist in the general population including a genetic predispo-
sition, environmental effects, stressful family events, early nicotine or other substance
use, psychological distress and co-occurring emotional (i.e., depression) and behavioral
conditions (i.e., ADHD, conduct disorder and anti-social personality disorder). Additional
risk determinants that are more likely to be relevant in autistic individuals include low
social support, dysfunctional coping strategies and poorer executive functioning. Social
isolation compounded by social communication deficits may lead to difficulties with self-
management, including a higher risk for establishing a pattern of substance abuse. The
evidence suggests that autistic persons are at increased risk for developing substance use
disorders, potentially via self-medicating with the goal of seeking relief from the multitude
stressors they are commonly faced with or using drugs or alcohol to calm social anxiety or
reduce the stress experienced in social interactions [49].
Genes 2023, 14, 677 6 of 21

2.1.9. Catatonia
Catatonia is a neuropsychiatric syndrome which has two subtypes. The akinetic (or
retarded) type is the most frequent one and is characterized by a slowing or reduction of
motor movements, immobility, rigidity, staring, mutism, withdrawal or refusal to eat. It
may also include bizarre features such as posturing, grimacing, negativism, waxy flexibility,
echolalia, echopraxia, stereotypy, verbigeration and automatic obedience. Hyperkinetic
(or excited) catatonia is a less common presentation, in which there are prolonged periods
of psychomotor agitation characterized by rigidity, autonomic dysregulation and altered
mental status, and it can lead to life-threatening complications, including death, if it is not
rapidly identified and treated [50].
There is an increased risk for catatonia in ASD, as well as other neurodevelopmental
disorders, compared to that of the general population, occurring most often in adolescence
and young adulthood [51]. Diagnostic challenges exist when catatonia develops in the
context of autism given the overlap of behavioral features between the two conditions.
Catatonic symptoms, including mutism, stereotypic speech, repetitive behaviors, echolalia,
posturing, mannerisms, purposeless agitation and rigidity, can be mis-identified as core
features of ASD [52]. Catatonia should be considered in autistic individuals when there
is an obvious and marked deterioration in movement, vocalizations, pattern of activities,
self-care and daily life skills. When accurately diagnosed catatonia can be medically treated
in a timely manner, improved outcomes are demonstrated, and a full recovery is seen in
most cases [53].

2.1.10. Psychosis and Schizophrenia Spectrum Disorders

Psychosis is defined by a loss of reality orientation, with symptoms including halluci-
nations, paranoid or delusional thoughts (defined as fixed, false beliefs), and can occur as a
result of a coexisting medical or psychiatric disorder. It is assumed that there is an underly-
ing vulnerability to developing psychosis in ASD, which is likely related to overlapping
genetic findings in ASD and primary psychotic (schizophrenia spectrum) disorders [54].
The risk factors for developing psychosis in ASD, when present, include major depressive
disorder, anxiety disorders and the emotional trauma caused by bullying and other victim-
ization, social bias, discrimination, unemployment, disability or other stressors commonly
experienced by autistic individuals.
Schizophrenia is a serious and chronic mental illness that, in addition to psychotic
symptoms, is defined by cognitive impairments, as well as persistently disordered ideas,
beliefs, perceptions and behaviors [55]. Zheng et al. conducted a systematic review and
meta-analysis of studies published over 10 years, demonstrating a significantly increased
prevalence of schizophrenia in ASD [56]. The overlap in clinical features, which can
superficially appear to be similar between ASD and schizophrenia, increases the possibility
of a mistaken diagnoses. The idiosyncratic ideas of a person with ASD, for example, can be
mistaken for the delusional beliefs which occur in psychosis. Likewise, cognitive rigidity
and behavioral inflexibility in ASD can be interpreted as delusional in nature, potentially
leading to a misdiagnosis of mental illness [57].

3. Genetics, Evaluation, Conditions and Genetic Testing in Autism

Advances in genetic technology and testing used to identify causation in patients with
ASD have led to the identification of a specific etiology in 40% of patients presenting for
genetic services using a three-tiered clinical genetics approach [58,59], in which genetic
syndromes, molecular and cytogenetic defects and metabolic disturbances were evaluated.
For example, mitochondrial disorders may account for up to 20% of individuals with
ASD [60], along with involvement of other metabolic disturbances such as untreated PKU
and Smith–Lemli–Opitz syndrome [11].
Children with ASD are also reported with microdeletions or duplications at the chro-
mosome level for chromosome regions 1q24.2, 2q37.3, 3p26.2, 4q34.2, 6q24.3, 7q35, 13q13.2-
q22, 15q11-q13, 15q22, 16p11.2, 17p11.2, 22q11, 2q13 and Xp22 [61]. Additional cytogenetic
Genes 2023, 14, 677 7 of 21

disorders have been found with new ultra-high-resolution microarray technology, includ-
ing the emerging 15q11.2 BP1-BP2 deletions and duplications [10]. GWAS findings in
ASD and broad autism phenotypes in extended pedigrees were studied in large cohorts
in Canada and the United States showing other chromosome regions such as 1p36.22,
2p13.1, 6q27, 8q24.22, 9p21.3, 9q31.2, 12p13.31, 16p13.2 and 18q21.1 [62]. Further studies
in ASD include the 15q11-q13 deletion (either of maternal origin as seen in Angelman
syndrome or paternal origin in Prader-Willi syndrome), the 15q11.2 BP1-BP2 deletion
(Burnside–Butler) syndrome or other chromosome 15 defects such as15q duplications or
marker chromosome 15s. Recognized genetic disorders with chromosomal defects include
Turner (45,X), Down (trisomy 21), Williams (chromosome 7q11.2 deletion), Smith-Magenis
(17p11.2 deletion), Shprintzen/velocardiofacial (22q11 deletion) and Phelan-McDermid
(22q13 deletion) syndromes.
Single gene disorders which include both autosomal and X-linked defects associated
with autism as a feature include tuberous sclerosis (TSC1 and TSC2 genes), neurofibro-
matosis (NF1 and NF2 genes), X-linked Rett (MECP2 gene) and fragile X (FMR1 gene)
syndromes. Other syndromic conditions associated with autism include Sotos, Noonan,
Moebius, Cohen, De Lange, Joubert, myotonic dystrophy and oculo-auriculo-vertebral
spectrum, along with PTEN gene disturbances with extreme macrocephaly [11,63,64]. Fi-
nally, environmental factors known to contribute to ASD include parental age, perinatal
factors, sex steroids, maternal health and maternal nutrition, as well as fetal exposure
to drugs, toxins, alcohol, smoking, maternal diseases and infections [65]. Therefore, an
environmental history should be obtained when one is pursuing potential contributing
factors in the cause of autism when the patient is presenting for evaluation and testing.

3.1. Genetic Considerations in Autism

3.1.1. Genetics, Clinical Evaluation and Genetic Testing of ASD
ASD is on the rise around the world and reported at a higher rate than congenital
defects such as brain malformations or for Down Syndrome are [66,67]. In 2018, the Center
for Disease Control and Prevention reported that 1 out of 44 children (2.2% of 8-year-
old children across 11 sites in the USA, based on health and education records) met the
diagnostic criteria for ASD ([Link]
html (accessed on 30 October 2022)). As a spectrum disorder, a wide range of associated
clinical conditions and deficits have been noted, particularly involving emotional self-
regulation and social skills, with as many as 30% of individuals with ASD not speaking.
Verbal and non-verbal communication impairments are common in ASD and impact the
development and maintenance of relationships. Differences involving the experience of
intensity, regarding idiosyncratic or highly focused interests and unusual responses to
sensory inputs, are generally noted beginning in early childhood, however a diagnostic
evaluation for ASD may not be sought for an extended period of time.
Autism is recognized as the most heritable neurodevelopmental disorder, with monozy-
gotic twins having concordance rates that are about three times greater than those for
dizygotic twins (0.98 and 0.53, respectively) [68,69]. Studies of multiple families and types
of twinning indicate the importance of genetics in the causation of ASD. The best estimate
for heritability is 80% reported in a review of more than two million individuals from six
hundred and eighty thousand families from multiple countries indicating that the study
of genomics can become a medical marker for ASD [70]. About 10% of individuals with
autism are from families without a positive family history, referred to as simplex or spo-
radic autism, and are due to ASD gene defects including deletions or duplications found
when they are studied at the chromosome level, particularly using chromosome microarray
analysis. Microarrays are comprised of DNA probes for identifying copy number variants
(CNVs) [71]. Individuals with autism and a positive family history are referred to as
multiplex people. They are more likely to show more individual defects at the gene level
(mutations) compared with those of typically developing children studied as controls, but
not at the larger chromosome level with microarray analysis. The majority of CNVs are
Genes 2023, 14, 677 8 of 21

due to chromosomal deletions involving single or multiple gene conditions found in about
20% of individuals with ASD. Both genome-wide association studies (GWAS) and genetic
linkage analysis have identified hundreds of DNA polymorphisms clustered in ASD risk
gene loci recognized on all chromosomes and within the human genome, consisting of
around 20,000 genes [9].
Chromosomal microarray analysis has demonstrated the highest diagnostic yield
in individuals with ASD compared to those of other genetic tests, but advanced next-
generation sequencing is continuing to identify other subtle genetic changes that have
not been detected with microarray analysis. High-resolution microarrays utilize both
CNV and polymorphic DNA probes to test for structural chromosome patterns such as
deletions/duplications or heterozygosity patterns in patients with neurodevelopmental
disorders including ASD. Microarrays are considered to be a first-tier genetic test and are
best utilized to identify deletions or duplications of multiple or single genes that might
be implicated at the chromosome level. For example, Ho et al. [10] in 2016 summarized
the results of ultra-high-resolution microarray testing of patients presenting with neu-
rodevelopmental disorders and/or autism for genetic services in a commercial laboratory
setting. They used 2.8 million CNV and single nucleotide polymorphic (SNP) DNA probes
optimized for neurodevelopmental disorders, reporting an overall CNV detection rate of
28.1% in 10,351 consecutive patients (average age 7 years, M:F ratio 2.5:1), with the overall
detection rate for individuals with ASD being significant at 24.4%. In those with ASD,
the most common cytogenetic abnormality was a 15q11.2 BP1–BP2 deletion (see
Genes 2023, 14, x FOR PEER REVIEW
Figure 1).
9 of 22
Those with neurodevelopmental disabilities without ASD showed that the 22q11.2 deletion
is the most common finding. Overall, 85 genetic findings were identified, with 9% of them
having the 15q11.2 BP1-BP2 deletion, followed by 16p11.2 deletion at 5% and 16p11.2
gene frequency, supporting an X-linked affected male-to-female ratio of 4:1 for autism.
duplication at 5%. Other findings included the 15q13.3 deletion, 16p13.1 duplication and
These findings may inform diagnosis and gene-based personalized care to allow more
NRXN1 gene deletion,
accurate genetic all at for
counseling 4%at-risk
(see Figure
family2).
members.

Figure 1. The relative frequencies of diagnoses in the combined ASD (n = 5694) and non-ASD (n =
Figure 1. The relative frequencies of diagnoses in the combined ASD (n = 5694) and non-ASD
4657) patient cohorts presenting for genetic services and laboratory testing using ultra-high-resolu-
(n =tion
4657) patient cohorts
chromosomal presenting
microarray analysisfor geneticwith
(reprinted services and laboratory
permission testing
from Ho et al. [10]). using ultra-high-
resolution chromosomal microarray analysis (reprinted with permission from Ho et al. [10]).
Genes 2023, 14, x FOR PEER REVIEW 10 of 22
Genes 2023, 14, 677 9 of 21

Figure
Figure2. 2.
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chart showing
chart showing thethe
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genetic findings
genetic using
findings ultra-high-resolution
using chromosomal
ultra-high-resolution chromosomal
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froma large cohort
a large cohortofof
over 10,000
over consecutive
10,000 consecutivepatients presenting
patients forfor
presenting genetic services
genetic services
and laboratory testing with neurodevelopmental disorders affecting brain function and/or struc-
and laboratory testing with neurodevelopmental disorders affecting brain function and/or structure
ture problems of unknown cause with developmental/intellectual disabilities and/or ASD with
problems of unknown cause with developmental/intellectual disabilities and/or ASD with data
data previously summarized by Ho et al. [10] (reprinted with permission from Genovese and But-
previously summarized by Ho et al. [10] (reprinted with permission from Genovese and Butler [11]).
ler [11]).
3.1.2. Known and Putative Genetic Determinants of ASD
Mammalian or human chromosomes, over the course of evolution, have become sub-
Our understanding of both the concept and causation of autism has exponentially
stantially complex with the assembly and configuration status for a specific chromosome
improved since Leo Kanner’s first clinical descriptions in 1943 [24]. Butler et al. [9] searched
influencing
the medical gene expression
literature and by their chromatin
identified about 800 structure
clinicallyand architecture.
known, relevantTheorconfigura-
susceptible
tion
genes reported in autism, compiled a master list of genes for ASD identified in theposition,
of each chromosome is based on its size, banding pattern and centromere literature
which in turn mayevidence
with supporting influencefrom access,
peerexpression
reviewedand function
medical at the by
resources individual
searchinggene level.
keywords
Genes are compartmentalized or packaged within chromosomes,
related to autism and genetics and plotted their location on chromosome ideograms. The and the architecture arelist
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chromosome 6, thus chromosome X has about 50% higher gene frequency, regions may play a larger role
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stantially complex with the assembly and configuration status for a specific chromosome bands. ASD genes
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packagedfor gene chromosomes,
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areOver the pastby40chromosomal
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staining, technology
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chromosome of specificas
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heterochromatic or darkly G-positive stained or euchromatic or lightly G-negative stained
Genes 2023, 14, 677 10 of 21

bands. The location of ASD genes in G-negative or G-positive bands was investigated
by McGuire et al. [72]. Genes located in the heterochromatin regions may play a larger
role in different biological processes than the genes located in euchromatic or active-gene
rich regions on the chromosome do. Physical measurements of established chromosome
banded ideograms were made based on chromosome size and appearance. Euchromatic
G-negative band regions contain 60% of the known protein coding genes, while the re-
maining 40% are distributed across the G-positive heterochromatin bands. ASD genes
were disproportionately over-represented in the darker heterochromatin sub-bands. This
distribution and location of ASD genes may allow us to obtain a better understanding of
neurodevelopment and function specifically associated with ASD genes and their locations
on chromosomes impacting availability for gene expression [72].
Over the past 40 years, advances in genomics technology with bioinformatics and a
rapidly growing interest in genetics research has led to discoveries of specific chromosomal
and gene defects and dozens of recognized genetic syndromes associated with autism.
For example, inborn errors of metabolism identified in individuals with autism include
adenylate succinase deficiency, lactic acidosis and mitochondrial DNA defects or dysfunc-
tion. The mitochondria are organelles found in the cytoplasm that play an important role
in adenosine 50 triphosphate (ATP) production required for energy utilization through
oxidative phosphorylation carried out by the electron transport chain made up of Com-
plexes I, II, III and IV found in the inner membrane of the mitochondria, containing about
100 proteins [60,73–75]. These proteins are encoded by both mitochondrial DNA (mtDNA)
and hundreds of interactive nuclear genes required for cellular energy influencing neu-
rodevelopment and brain function. Several types of mitochondrial defects exist, including
a depletion form with a reduced number of mitochondria per cell affecting biochemical
reactions within the mitochondria and individual cells, particularly those requiring more
energy to carry out their functions such as the brain and muscles [60,67,76,77]. In humans,
from 100 to 10,000 separate copies of mtDNA are usually present per cell, while some cells
such as germ-line ones may have many more copies required for energy production. Inborn
errors of metabolism are recognized as the causes of enzyme deficiencies, leading to an
accumulation of substrates or substances that can be toxic to the developing brain.

3.1.3. Molecular Genetic Characterization and ASD

During the last decade an enormous number of published molecular genetic reports
on autism have utilized in genomic technology, bioinformatics and computational biol-
ogy, including genome-wide association studies (GWAS) across the fields of medicine,
psychiatry and the social sciences. This research led to the interrogation of genomic vari-
ants to search for links among specific gene findings, disorders, traits or phenotypes of
affected individuals. Furthermore, bioinformatics and computational biology software
interactive programs combined with human genomic datasets have led to the discovery of
gene-gene–protein interactions, biological pathways and molecular functions and a further
understanding of the role of genetics and biology in neurodevelopment.
Early GWAS analyses have found a strong association with single nucleotide polymor-
phisms (SNPs) and cadherin genes, including neuronal cell adhesion molecules with over
100 genetic loci reported with ASD [78,79]. More recent data indicate that over 2000 human
genes are implicated in intellectual developmental disability and ASD [80]. Many ASD
genes are located on the X chromosome (>150 out of 900 X-linked protein coding genes)
and involved in chromatin remodeling, synaptic function, neuronal signaling and brain
neurodevelopment [81]. Of the 800 genes implicated as clinically relevant ones that are
known or susceptible in ASD [9], many include members of the neuro-ligand, neurexin,
cadherin, GABA receptors and SHANK gene families. Other genes encode neurotransmit-
ters and their receptors, transporters, brain-derived hormones, oncogenes, signaling and
ubiquitin pathway proteins, neuronal cell adhesion molecules and epigenetics [9,82,83].
One of the ubiquitin related genes is UBE3A (ubiquitin protein ligase E3A), a mater-
nally expressed gene on chromosome 15 that causes Angelman syndrome, an imprinted
Genes 2023, 14, 677 11 of 21

disorder, and when it is mutated, it shows features of autism [84]. Therefore, gene ex-
pression patterns and correlation with features of autism were studied in individuals
with chromosome 15 disorders (Angelman, Prader-Willi and chromosome 15 duplication
syndromes), including UBE3A gene and SNORD116, a paternally expressed transcript or
snoRNA that serves as a precursor to the antisense UBE3A gene for regulation of its activity.
The reported findings suggested the presence of novel interactions between expression
of UBE3A and SNORD116, with brain specific processes underlying motor and language
impairments in autism and these chromosome 15 imprinted genetic disorders.
Next-generation sequencing now enables the accurate detection of mutations or gene
variants at the whole exome or genome level by sequencing nuclear and mitochondrial
DNA, and is, therefore, potentially more informative than structural chromosome mi-
croarrays are for single gene changes. Newer chromosomal SNP microarrays can identify
chromosome abnormalities at levels approximately 100 times smaller than those seen with
standard high-resolution chromosome methods developed in the 1980s. In terms of evi-
dence, Shen et al. [85] reported genetic findings from more than 900 patients presenting
with ASD using standard karyotype chromosome analysis, fragile X DNA testing (Fragile X
Syndrome is recognized as the most common cause of familial intellectual disability and/or
autism, primarily affecting males) and chromosomal microarrays. They found abnormal
karyotypes in 2.2% of the patients, abnormal fragile X testing in 0.5% and deletions or du-
plications in 18.2%, including recurrent chromosome deletions or duplications for 16p11.2,
15q13.2-q13.3, 7q11 and 22q11.2, and more recently, 15q11.2 BP1-BP2 [10,11,86].
Whole exome sequencing (WES) has yielded results ranging between 9 and 30% [11,87,88]
in individuals with ASD. For example, Aspromonte et al. [89] studied intellectual disability
and autism with next-generation sequencing using a panel of 74 genes involved in molec-
ular pathways and pathogenesis of both intellectual disability and ASD in 150 patients,
achieving a 27% total diagnostic yield. One of the largest exome sequencing studies in
autism to date was conducted by Satterstrom et al. in 2020 [90] in nearly 12,000 individuals
with autism, including proband–parent trios and controls implicated 102 autism risk genes,
finding a significant 3.5 fold increase in the de novo protein truncating variants in their
study population. However, most of the gene variants found in other studies were of
unknown clinical significance and were not reported in the medical literature as disease-
causing ones or included in human genomic databases. These variants were rarely reported
as pathogenic or likely pathogenic due to limitations in bioinformatics, computational
prediction or the paucity of data in the literature. A recognized complex interplay exists
between inheritance and environmental factors that contribute to autism and is impacted
by epigenetic regulation of gene expression. With improvements in genomic technology,
bioinformatics, computational predictions and the enlarging of human genomic databases,
more useful information will be learned about the genetic causation of and single gene
findings for ASD.

3.1.4. Genetic Technologies Advance Our Understanding of ASD

A better understanding of how variations in implicated genes influence the presence
of co-occurring conditions and drug response is needed, particularly as this information
can help to guide personalized treatment approaches for ASD. Veatch et al. [91], in 2020,
established a protocol to pinpoint ASD genes that are more likely to have clinically relevant
variants by developing a functional annotation pipeline. They began with a list of all
the candidate genes implicated in recognized manifestations of ASD utilizing databases
that represent multiple lines of evidence including genes expressed in the human brain
involved in ASD, their relevant biological processes and phenotypes reported in mice,
whose products possess certain pharmacogenetic variation, have been targeted by pharma-
ceutical agents or directly interact with specific genes having variants recommended to be
tested for by the American College of Medical Genetics (ACMG). Of 956 ASD implicated
genes studied in the full set, 18 were flagged based on evidence from all the categories,
with notably none of the prioritized genes represented among the 59 genes compiled by
Genes 2023, 14, 677 12 of 21

ACMG, and 78% with a pathogenic or likely pathogenic classified disease-causing variant.
This ongoing research should rapidly prioritize potentially actionable results from genetic
studies and, in turn, inform clinical decision support for personalized care based on genetic
testing.
Butler et al. [92] utilized early advances in genetic technology and a bioinformatics
approach in a group of 20 females with autism (average age 7.7 years, range from 5 to
16 years) from multiplex families and compared them to simplex or sporadic families,
indicating single gene involvement with structural DNA changes. Five of the twenty
females had functional variants of X-linked genes (IL1RAPL1, PIR, GABRQ, GPRASP2 and
SYTL4) along with cadherin, protocadherin and ankyrin repeat gene families (CDH6, FAT2,
PCDH8, CTNNA3 and ANKRD11) and other related genes for neurogenesis or migration
(e.g., SEMA3F and MIDN). More recently, a report using next-generation sequencing data
and a meta-analysis of the literature compared ASD, epilepsy and intellectual disability
identified in 103 published studies (ASD, N = 14; epilepsy, N = 72; intellectual disability,
N = 21) across 32,331 individuals with diagnostic yields of 17.1% for ASD, 24% for epilepsy
and 28.2% for intellectual disability [93]. The meta-analysis yielded a similar result to that
of the whole exome study in the female ASD cohort reported earlier by Butler et al. [92].
More research is needed to identify the most commonly cited genes and their gene-gene–
protein interactions with pathway analysis to introduce new avenues for therapeutic agents
and treatment.
Complex inheritance patterns exist in neuropsychiatric illnesses, indicating multiple
genetic and environmental factors influencing disease risk and course. Hence, the GeneAn-
alytics computer program was used to conduct a pathway analysis and genetic profiling
with predictors to characterize common or susceptible genes for ASD (792 genes [9], bipolar
disorder (290 genes [94]) and schizophrenia (560 genes [95]). This program utilized an
analytical approach to compare and rank score the number and nature of overlapping
genes among disorders, gene disease associations and pathways, gene functions and tis-
sue specificity, subdivided into categories (e.g., diseases, tissues or functional pathway).
Twenty-three genes were found to be common among all three disorders and mapped
to nine biological superpathways. These included circadian entrainment with ten genes,
amphetamine addiction with five genes and sudden infant death syndrome with six genes.
The program identified brain tissues with involvement in gene activity and measures for
the three disorders involving the medulla oblongata with eleven genes, thalamus with ten
genes and hypothalamus with nine genes. Six common genes were also found including
BDNF, DRD2, CHRNA7, HTR2A, SLC6A3 and TPH2. Interestingly, these overlapping genes
impact serotonin and dopamine homeostasis and signal transduction pathways affecting
mood, behavior and physical activity. Converging effects were also recognized in pathways
that govern circadian rhythms with 10 genes found in common (SLC6A3, GSK3B, HTR2A,
MAOA, NOS1AP, PDE4B, TPH2, CACNA1C, CHRNA7 and DRD2) and supported by a
known core etiological relationship that exists between neuropsychiatric illnesses and sleep
disruption with hypoxia and associated central brain stem dysfunction [82,96].
In summary, a total of 106 phenotypes were mapped to the 23 overlapping genes, with
36 phenotypes in common including 18 genes having highly matched ranking scores. The
highest matched phenotypes were behavioral despair (learned helplessness) involving four
genes in common, hypoactivity involving seven genes, abnormal serotonin levels involv-
ing four genes and abnormal response to novel objects involving four genes. Addition-
ally, identified phenotypes impact GABAergic neuron morphology, synaptic transmission
and a response to hypoxia and a risk of death. Of the three disorders with overlapping
genes matched to superpathways, the circadian entrainment category was the number one
matched finding, followed by amphetamine addiction. For the biological processes category,
the startle response was ranked as number one, followed by positive regulation of axon
extension, cellular calcium ion homeostasis, synaptic transmission, dopamine catabolic
process and axon guidance with synapse assembly [80]. Three functional pathways de-
scribed in ASD as potentially involved were chromatin remodeling (e.g., CHD7, MECP2,
Genes 2023, 14, 677 13 of 21

DNMT3A and PHF2), the Wnt pathway (e.g., CHDF8, PAX5 and ATRX), other signaling
superpathways (e.g., GPCR, ERK and RET) and mitochondrial dysfunction [82,96].
Bipolar disorder and schizophrenia share certain neuropsychiatric and behavioral
disturbances with ASD, including atypical styles of social interaction and communication,
cognitive and perceptual differences and sleep disturbances. Multiple overlapping genetic
and environmental influences may implicate the risk of disease, as demonstrated by an
increased likelihood of either schizophrenia or bipolar disorder in first-degree relatives [95],
and a 3.6 fold elevated risk in those diagnosed as children with ASD for developing
schizophrenia as adults. Conversely, the prevalence of ASD in individuals diagnosed with
schizophrenia is significantly elevated compared with population norms [97,98].

3.1.5. Treatable Medical, Neurological/Neurometabolic Conditions, Intellectual Disabilities

and ASD
A defective PTEN gene was reported in about 20% of individuals with autism and
macrocephaly, a common finding in ASD [63]. PTEN is an important tumor suppressor
gene reported to play a role in tumor growth, hamartoma disorders, overgrowth and
cancer [98–101]. Gabrielli et al. [101] utilized the GeneAnalytics pathways and gene pro-
filing computer program to examine shared autism and cancer genes, which is related to
earlier research demonstrating that individuals with ASD had abnormal neuronal growth
patterns with an overabundance of dendritic spine profiles. They found that 17% of the
800 ASD genes overlap with recognized cancer genes involving 371 superpathways for
major cell signaling and metabolic disorders (e.g., CREB, AKT and GPCR), along with
153 gene ontology (GO) biological processes, 41 GO molecular functions and 145 matched
phenotypes. Several of these pathways and molecular mechanisms proposed a cross-talk
between the canonical Wnt pathway and the Notch signaling cascade with other disturbed
genes and interactions [90,102–104]. These pathways may play a central role in a wide
range of biological processes and when they are abnormal, they may compromise biolog-
ical output or function contributing to neuropsychiatric disorders, cell growth and even
malignancy in autism.
There is a growing list of over 1400 recognized inherited neurological and neu-
rometabolic conditions (Inborn Errors of Metabolism Knowledgebase (IEMbase). (www.
[Link] (accessed on 10 December 2020)) causing intellectual disability that may also
impact ASD, as recently reviewed by van Konijnenburg et al. [16]. They queried databases
include PUBMED, OMIM and Orphanet, identifying 116 treatable inherited metabolic
disorders, finding 139 genes accounting for 116 disorders, for which the most frequent
therapeutic interventions were pharmacological or nutritional based, with vitamins and
trace element supplementation. Other treatment plans included organ or stem cell trans-
plantation, enzyme replacement and gene-based therapies, with reported treatment effects
including the improvement of clinical deterioration (62%), neurological manifestations
(47%) and development (37%).
The first tier of laboratory testing recommends the non-targeted metabolic screening
of fasting blood samples to rule out disturbances of unexplained developmental delay,
intellectual disability and ASD. These tests include those on fasting blood lactate, folate,
ammonia, copper, amino acids, total homocysteine, acylcarnitines, very long chain fatty
acids, transferrin N-glycan profiling and urine samples for organic acids, oligosaccharides,
creatine, glycosaminoglycans and guanidinoacetate levels, accounting for 59% or 69 of the
treatable metabolic disorders. Along with this first tier testing, genetic laboratory evaluation
is recommended to include exome sequencing and mitochondrial DNA testing to target
a growing list of causative genes contributing to the 116 disorders involving 139 genes,
as well as targeting molecular results in 37 genes without biomarkers, accounting for 23
of the 116 recognized intellectual disability disorders. For these 23 disorders, no specific
biomarker is currently available, and molecular testing would be required for 20% of the
treatable disorders [16].
Genes 2023, 14, 677 14 of 21

A second tier would target metabolic testing to identify 24 disorders, or 21%, includ-
ing access to cerebral spinal fluid, enzymatic assays, or urine purines and pyrimidines.
Treatable disorders are categorized as vitamin and cofactor metabolism (25%), amino acid
metabolism (24%), complex molecular degradation (9%), neurotransmitters (8%), nucleic
acid disturbances (6%), glycosylation defects (5%), energy substrate metabolism (4%),
trace metals and elements (4%), carnitine, fatty acid and ketone body metabolism defects
(4%), lipid metabolism (3%), mitochondrial cofactor biosynthesis defects (2%), other disor-
ders mitochondrial dysfunction (2%), and carbohydrate metabolism, peptide and amine
metabolism, endocrine metabolic disorders, mitochondrial DNA-related disorders and
nuclear-encoded disorders of oxidative phosphorylation defects (all at 1% each). More than
one third of the known treatable intellectual disability disorders included in the current
literature were identified during the past eight years, with the majority of the effective
treatments based on nutritional interventions considered to be relatively less expensive
and more widely available than other options such as enzyme replacement are [16].
Examples of inherited metabolic disorders impacting neurodevelopment and function
are numerous, with all modes of inheritance (e.g., autosomal dominant, autosomal recessive
and X-linked). Clinical treatments have helped to halt or slow down disease progression
(62%), impaired neurological manifestations (47%), systemic manifestations (44%) and
psychomotor or cognitive development (37%), prevented acute metabolic decompensation
(30%), improved seizure/epilepsy control (22%) and improved psychiatric disturbances
(21%) [16]. Inherited metabolic disorders include disorders of glycosylation (e.g., SLC35A2-
CDG); amino acid metabolism (e.g., carbamoyl phosphate synthetase 1 deficiency); complex
molecule degradation (e.g., α-mannosidase deficiency); energy substrate metabolism (e.g.,
creatine transporter deficiency); carbohydrate metabolism (e.g., GLUT1 deficiency); fatty
acid, carnitine and ketone body metabolism (e.g., mitochondrial acetoaceyl-CoA thiolase
deficiency); lipid metabolism (e.g., 7-dehydrocholesterol eductase deficiency); nucleic acid
metabolism (e.g., phosphoribosylpyrophosohate synthetase deficiency); trace metals (e.g.,
Wilson disease); vitamin and cofactor metabolism (e.g., methylmalonic aciduria); mitochon-
drial myopathy; neurotransmitter disorders (e.g., tyrosine hydroxylase deficiency).
An example of an autosomal dominant genetic disorder associated with an increased
risk of developing autism, for which there are potentially effective treatment options, is
tuberous sclerosis, which is caused by defects of the TSC1 or TSC2 genes [101,105]. Tuberous
sclerosis is a classical genetic disorder with neurodevelopmental problems, seizures, renal
angiomyolipomas, astrocytomas, skin depigmentation, ADHD and autism ([Link]
OMIM #191100). Kilincaslan et al. [105] reported on the beneficial effects of everolimus
medication on autism and ADHD in patients with tuberous sclerosis. This drug inhibits
mTOR, one of the top thirty biological super-pathways identified when comparing shared
autism and cancer genes [101]. The effects of this drug on neuropsychiatric findings in
those with autism require more testing.

3.1.6. Pharmacogenetics with Medication Management and Selection

Precision or personalized medicine is an emerging tool for use in clinical practice,
which leads to improved medication selection and management based on an individual’s
DNA pattern or pharmacogenetics [106]. The study of pharmacogenetics is based on
structural DNA variation at the individual level that impacts the drug metabolism and
therapeutic response based on the cytochrome P450 liver enzyme system, which is coded
by individual genes throughout the human genome. Cytochrome P450 enzymes metabolize
medications by the liver and influence drug concentrations in the blood. Most prescription
drugs are metabolized by this enzyme system, and therefore, it plays a significant role in
treatment success. The identification of specific cytochrome P450 gene polymorphisms
can explain the source of variability in drug dosing and response, thus helping to guide
effective treatments for individuals with ASD.
There are over 50 cytochrome P450 liver enzymes that metabolize endogenous and
xenobiotic substrates, including environmental pollutants and plant-based chemicals. These
Genes 2023, 14, 677 15 of 21

enzymes are also involved in the biosynthesis and metabolism of steroids, vitamins, hor-
mones, lipids and prostaglandins [107–112]. About 90 percent of all drugs are metabolized
by seven different liver enzymes including CYP1A2, CYP3A4, CYP3A5, CYPC19, CYP2D6,
CYP2C9 and CYP2B6 [104]. The most common medications used to treat patients with
psychiatric or behavioral problems including ASD are metabolized by CYP2D6 [106–109].
Often drugs are metabolized by more than one cytochrome P450 enzyme, and some drugs
such as risperidone require them to be broken down from an inactive drug or compound
to generate an active metabolite or functional agent for treatment. Individuals who are
either fast or slow metabolizers based on the cytochrome P450 system DNA patterns who
take psychotropic drugs may respond differently to the recommended dosage, thereby
producing adverse side effects or a lack of response. A better understanding of metabolic
differences that occur with age and increased use of medications may further impact drug
dosage and the selection of specific drugs for treatment.
Clinical trials investigating new classes of drugs or advances being achieved in research
on existing drugs for new purposes, including the treatment of behavior problems in ASD,
are ongoing and hold promise for the discovery of improved therapies. Other important
factors that may also play a role in the efficacy of medications in treating diseases or
disorders include neurotransmitter receptors, cell membrane transporters and sensitivity
markers, which vary from person to person and are coded by individual genes outside of
the cytochrome P450 enzymes [107].
There is growing evidence that the cytochrome P450 enzymes may be altered by
drugs or other substances that act as either inducers or inhibitors, as well as drug–drug
interactions. Known inhibitors or inducers may include common sources in the diet such
as grapefruit, broccoli, cabbage, cauliflower or coffee. All potential sources of inducers or
inhibitors should be considered, along with knowledge of the individual’s enzyme activity.
For example, reduced cytochrome P450 enzyme activity could be positively impacted
by an inducer (a food source or drug) and increase the enzyme response in breaking
down or metabolizing a drug prescribed to treat the patient, thus altering the therapeutic
response. The person’s individual DNA pattern that encodes the liver enzymes involved
in metabolism to generate a fast or slow metabolic rate regarding drug break down and
treatment response can either negate the potential benefit of drug therapy and/or lead to
adverse side effects. Drug–drug interactions and plasma drug concentration adjusted by
half-life in accordance with response to inhibitors and/or inducers can also impact the
medication levels and treatment success [105–109].
About 25 to 50% of individuals do not respond as they are expected to, to recom-
mended drug dosages or other therapeutic treatment interventions, and this scenario also
applies to those with ASD. The discovery of new classes of medications and research on
existing drugs for new purposes to treat behavioral, psychiatric and medical conditions in
patients with ASD are under investigation, with the goal expanding the treatment options
and improving treatment outcomes. In addition, the application of genetic advances that
improve our understanding of pharmacogenomics and gene-gene–protein interactions
along with pathway and functional analysis may help to lead to new discoveries and
applications for therapeutic interventions in ASD [111].

4. Limitations
The limitations noted include a relative lack of data in the literature regarding behav-
ioral and psychiatric co-occurring conditions for adults, and particularly for older adults
with ASD, as well as for individuals with the dual diagnosis of ASD and intellectual devel-
opmental disabilities. The authors additionally note that the currently existing genomic
technology, bioinformatics and computational predictions, as well as the size of available
human genomic databases and published information, limit what can be learned about
genetic causation and single gene findings in ASD. Finally, it is recognized that there are
limitations in the available research to date in identifying relevant genes, their variants and
gene-gene–protein interactions, as well as the clinical utility of existing pharmacogenomics
Genes 2023, 14, 677 16 of 21

testing, with improvements being needed to guide the selection of effective therapeutic
agents and other treatment interventions.

5. Conclusions
In this review, we discussed the behavioral and psychiatric conditions commonly
associated with autism, including irritability, aggression, self-injurious behaviors, ADHD,
anxiety, obsessive compulsive disorder, gender dysphoria, mood disorders, suicidality,
substance use disorders, catatonia, psychosis and schizophrenia. Genetic associations,
identified syndromes and chromosomal defects including deletions and duplications, and
gene variants associated with genetic contribution and high heritability estimates seen in
ASD were described and illustrated. The largest high-resolution chromosomal microarray
analysis of patients presenting with ASD for genetic laboratory services was 15q11.2 BP1-
BP2 deletion (Burnside–Butler) syndrome as the most frequent finding, followed by 16p11.2
deletion, accounting for a combined 14% of the 85 genetic defects [10,11].
Advanced genomic testing including exome sequencing and computational analy-
sis found several disturbed pathways and molecular mechanisms including chromatin
remodeling, Wnt, Notch and other signaling superpathways, PTEN, BDNF, NRNX1 and
SHANK3 and related genes involved in neurogenesis, metabolic problems and mitochon-
drial dysfunction. The genetic data analyzed using computer based programs found share
mechanisms that may lead to the identification of common pathologies, disturbed gene
and protein pathways, biological processes and molecular functions. This information may
lead to a better understanding of causation with potential treatment options to lessen the
severity of ASD-related challenging behaviors.
Finally, the authors describe the role of pharmacogenetics and testing, identifying
and defining variables impacting the metabolism of psychiatric medications for those
with ASD, thereby helping to guide therapeutic pharmacological interventions. More
studies are needed to further characterize the epiphenotypes within the autism spectrum,
the contribution of gene variants, chromosome aberrations, and identified syndromes
with potential treatable outcomes, with the goal of reducing comorbidities impacted by
pharmacogenetic patterns, neurometabolic disturbances and environmental factors. More
research could assist in earlier diagnoses, expand our understanding of causation and lead
to improved, tailor-made therapeutic interventions for each affected individual.

Author Contributions: M.G.B. and A.G. wrote, reviewed, and edited both the original and final ver-
sions of the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Informed Consent Statement: No consent required for this review article.
Data Availability Statement: No available data to share.
Acknowledgments: We thank Corina Fryman for assistance with manuscript preparation and submission.
Conflicts of Interest: There are no conflict of interest by the authors.

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