For citation purposes: Jensen RA. The background genetic effect of the genes underlying the broad autism phenotype as a unifying feature in gene x gene and gene x environment causal mechanisms in autism. OA Autism 2013 May 01;1(2):11.


Diagnosis Advancements

The background genetic effect of the genes underlying the broad autism phenotype as a unifying feature in gene × gene and gene × environment causal mechanisms in autism

RA Jensen*

Authors affiliations

6100 N. Brookline Ave, #27,Oklahoma City, OK 73112, USA.

*Corresponding author Email:



This model examines the role of proposed broader autism phenotype candidate genes and unfavourable pre-, peri-and neonatal factors and environmental hazards associated with risk for early disruption of brain development, organisation of neural circuitry and increased risk for autism. A number of designated autism susceptibility genes may be more robustly characterised as broader autism phenotype candidate genes. This review proposes five broader autism phenotype candidate genes (SLC6A4, COMT, CNTNAP2, MET, FOXP2) for further review. Phenotypes result from the expression of an organism’s genes as well as the influence of environmental factors and the interactions between the two. Broader autism phenotype candidate genes are pleotropic and include common heritable polymorphisms associated with general population risk for variable genotype-phenotype expressions that are frequently seen in autism, unaffected family members and in the general population. The general population broader autism phenotype candidate genes and genotype-phenotype expressions include social cognition and personality features, immune deficiencies, fine and gross motor incoordination, developmental language impairment, eating disorders, depr ession, anxiety and panic disorders, sensory processing impairments, obsessive compulsive behaviours, diabetes, gastrointestinal disorders, irritable bowel syndrome and repetitive behaviours that cluster within affected and unaffected family members and that are continuously and variably distributed throughout the general population. The independent broader autism phenotype component part is always reliant on other gene mutations inherited and/or de novo, environmental risk factors and epigenetic events acting alone or in concert that are involved in the transition to strictly defined autism. The general population risk for autism in developmentally compromised or at-risk individuals associated with a specific pre-, peri- or neonatal insult is calculated at about 7%. This review discusses the background genetic effect of the genes underlying the broad autism phenotype as a unifying feature in gene × gene and gene × environment causal mechanisms in autism.


Identifying unfavourable pre-, peri- and neonatal risk factors and environmental hazards associated with the severe developmental disorders (autism, intellectual disability, attention deficit hyperactivity disorderand schizophrenia) should be a high priority that might lead to more effective prevention strategies for these debilitating developmental conditions.


Autism is behaviourally defined by the Diagnostic and Statistical Manual, Fourth Edition, Text Revision[1] and involves a constellation of behavioural symptoms related to social cognition personality features, delayed, absent or unusual communication styles and stereotypical or obsessional and repetitive behaviours that fall under the umbrella category of the pervasive developmental disorders (PDD). The three major sub-categories are autistic disorder, PDD-Not Otherwise Specified and Asperger syndrome. In this review all sub-categories within the PDD’s are referred to as autism. Individuals diagnosed with autismand their unaffected family members may share many subtle qualitative similarities in social-cognitive personality features, language, sensory processing and repetitive behaviours that are thought to mirror some aspects of autism features but that are not associated with a debilitating neurodevelopmental condition. The broader autism phenotype (BAP) and associated features are continuously and variably distributed throughout the general population[2,3].

An emerging consensus suggests that the broad spectrum of developmental disorders, including autism, may involve an early, long-lasting disruption of brain development that interferes with pre-programmed neuronal migration and is disruptive of normal synaptic connectivity. Neuropathological and imaging studies have consistently reported microscopic and macroscopic structural anomalies in the brain in autism[4,5]. Genetic and environmental influences have been invoked but autism aetiology has proven to be elusive[6]. Heterogeneity and non-specificity in genetic, phenotypic, neuropathological, neuroimaging and environmental studies have emerged as a significant obstacle in advancing the understanding of the biological complexity and mechanisms underlying autism aetiology[7,8].

Two competing conceptual models for autism aetiology have been in place for decades. One model views autism aetiology primarily as a heritable genetic condition and the competing model views autism as primarily involving environmentally-induced structural anomalies in the brain.Both models associate autism with atypical brain development, however no single rare large genetic deletion or duplication, common genetic variant, unfavourable pre-, peri- or neonatal event or environmental hazard is predictive of autism. Autism is likely to involve multiple risk factors of small effect that in aggregate increases total risk in any individual case[9,10,11].

Rutter[12] has proposed a two-hit model and the existence of BAP candidate genes:

“In other words, what is required for autism ‘proper’ to develop are the susceptibility genes and some other risk factor that could be either genetic or environmental in origin. The implication, if it is a two hit process is that the genes underlying the broader autism phenotype may not be exactly the same as those involved in the transition to the handicapping disorder.”

The long-lasting disruption of early brain development is involved in the transition to a broad spectrum of diverse neurodevelopmental conditions including autism, ADHD, schizophrenia and intellectual disability (primary mechanism).The common heritable genetic polymorphisms underlying the BAP component part (secondary mechanism) is a background genetic effect that when present is determinative of a developmental trajectory towards an autism diagnosis. In early childhood during the long-lasting rapid disruption of brain development and organisation of brain circuitry occurs, an array of BAP genotype-phenotype expressions may interactively manifest themselves at the extremes in strictly diagnosed autism. The aim of this review was to discuss the background genetic effect of the genes underlying BAP as a unifying feature in gene × gene and gene × environment causal mechanisms in autism.

The BAP candidate genes

An increasing number of autism candidate genes have been proposed and common heritable gene polymorphisms that are distributed throughout the general population may be more robustly characterised as BAP candidate genes. BAP candidate genes harbour within them subunits of genetic variants associated with autism risk. BAP candidate genes are pleotropic. Phenotypes result from the expression of an organism’s genes as well as the influence of environmental factors and the interactions between the two. BAP candidate genes should include regions that harbour common genetic variants associated with general population risk for variable genotype-phenotypic expressions. General population genotype-phenotype expressions in BAP genes include unique social cognition and personality type features, immune deficiencies, fine and gross motor incoordination, developmental language impairment, eating disorders, depression, anxiety and panic disorders, bipolar disorder, sensory processing impairments, obsessive compulsive behaviours, diabetes, gastrointestinal disorders, irritable bowel syndromeand repetitive behaviours that cluster within strictly diagnosed autism, unaffected first-degree relatives in the families and in the general population.

The common genetic variants in the BAP candidate genes are heritable and very common in the general population. For example, the MET(7q31) gene region harbours a polymorphism, the MET promoter variant rs1858830 allele ‘C’, which is present in 47% of the general population and is associated with immune function, gastrointestinal repair, neuronal growth and development[13]. One of the first autism candidate genes proposed is the serotonin transporter gene SLC64A (5-HTT), which maps to chromosome 17q[11,12]. Multiple studies have implicated common genetic polymorphisms within the COMT gene (22q11) region as an autism candidate gene. One of the earliest target-rich regions containing autism candidate genes was mapped to chromosome 7 and include MET(7q31), CNTNAP2(7q35) and FOXP2(7q35).Extreme genotype-phenotype expressions in the BAP genes that harbour common polymorphisms may involve gene by environment or epigenetic mechanisms given how widely these polymorphisms are distributed throughout the general population. General population genotype-phenotype expressions in BAP proposed candidate genes are listed in Table 1.

Table 1

BAP candidate genes:genotype-phenotype expressions

In early childhood during the rapid and long-lasting disruption of early brain development, severe symptoms begin to emerge and an array of independent BAP component parts may be variably expressed at the extremes in strictly diagnosed autism. The BAP candidate genes all involve common polymorphisms associated with general population risk for obsessive compulsive disorder. In strictly diagnosed autism in early childhood, severe obsessive compulsive disorder-like symptoms may emerge including repetitively checking things, counting things, hoarding behaviours, lining up objects and amassing collections of objects. When these behaviours are disrupted severe anxiety and panic attacks are commonly observed[42]. Sensory impairments are seen and may include unusual responses to touch, light, sound, heat and pain[43]. Idiosyncratic feeding behaviours are frequently observed perhaps related to general population risk for eating disorders[24].Medical complications such as severe constipation, gastrointestinal problems, irritable bowel syndrome and immune deficienciesoccur more frequently than general population norms. Impairments in gross and fine motor skills are a commonplace[44].

The phenomenon of transient echolalia appears to be universal in verbal young children diagnosed with autism[45]. Echolalia has been seen in other conditions that feature aberrant neuronal circuitry including patients with Alzheimer disease, brain tumour and stroke[46,47,48].

General population prevalence of the BAP and at the extremes

The BAP social cognition features concept by child psychiatry has its origins in Leo Kanner’s[42] 1943 classic article ‘Autistic Disturbance of Affective Contact’. He described the parents as follows:

“One other fact stands out prominently. In the whole group, there are very few really warm hearted fathers and mothers. For the most part, the parents, grandparents and collaterals are persons strongly preoccupied with abstractions of a scientific, literary, or artistic nature, and limited in genuine interest in people.”

A number of groups have measured the general population prevalence of BAP social cognition, communication and repetitive traits by devising a check list of questionnaires including the Childhood Asperger Syndrome Test, the Autism Spectrum Questionnaire and the Social Reciprocity Scale. These checklists do not contain any biological symptoms that may cluster in affected and unaffected family members and in the general population that may also be associated with increased risk for disruption of early brain development.

Genetic epidemiology has measured the prevalence of BAP traits in the general population by recruiting thousands of volunteer samples often taken from twin registries with research questionnaires to be completed by parents or teachers or by self report. The studies have consistently reported that the prevalence of BAP traits are moderately to highly heritable and extend very broadly throughout the general population. Hoekstra et al.[49] measured the BAP using Autism-Spectrum Quotient scores from volunteers recruited from a twin registry and found the BAP to be highly heritable and continuously distributed showing substantial variability throughout the general population. Constantino & Todd[50] found sub-clinical autistic-like traits by parent-scored measures in the Social Responsiveness Scale to be highly to moderately heritable and also widely distributed throughout the general population. Ronald et al.[51] reported high heritability for extreme BAP traits and BAP traits as measured on a continuum. Preti et al.[52] reported on the self-administered Empathy Quotient test, thought to measure the prevalence of a putative BAP trait, empathy, taken by undergraduate students. A score below 30 represents the cut-off that best differentiates the presence of this putative BAP trait from controls. Of the 374 students (males=118, females=256) completing the test, 18 scored below the cut-off of 30 (males=11.9%, females=2.9%). About 20% of unaffected siblings have a history of language delay far greater than the 7.4% of general population children with a history of language delay[53,54].Ronald et al.[55] selected the top 5% highest BAP scorers and reported high heritability that showed modest phenotypic and genetic overlap between three measures: social impairments, communication impairments and restricted repetitive and interests. Happe and colleagues[56] reported that “Around 10% of all children showed only social impairment, only communicative difficulties or only rigid and repetitive interests and behaviour, and these problems appeared to be at a level of severity comparable to that found in children with diagnosed autism in our sample.”

The Rutter hypothesis was demonstrated in a gene × gene (G × G) causal mechanism, Down syndrome with autism, featuring the interplay between a de novo genetic mutation and a background BAP genetic effect that follows a developmental trajectory to an autism diagnosis. Ghaziuddin[57,58] compared a group of Down syndrome individuals and their first-degree relatives (parents and siblings) with or without a diagnosis of autism. In Down syndrome with autism there was an excess of first-degree relatives who met the description of BAP features compared to first-degree relatives in Down syndrome without autism who did not. The Down syndrome mutation and autism was not present in first-degree relatives, parents and siblings, and the genes underlying the BAP component part are independent of and are a background genetic effect secondary to the disruption of early brain development in Down syndromeand the transition to autism as predicted by the Rutter hypothesis.

Unfavourable pre-, peri- and neonatal factors in autism: gene × environment (G × E) causal mechanism

Several design methodologies examining obstetrical and environmental hazards associated with autism risk have been in place for decades. The most common design method is selecting autism diagnosed only individuals and largely unaffected sibling, neurotypical and/or national statistic controls. This method has produced consistent evidence that unfavourable events in the pre-, peri- and neonatal period may or may not be associated with autism risk. The data have been difficult to analyse as the factors representing possible risk for autism are not specific to autism and may represent various forms of pathological processes and developmental problems. No single unfavourable factor or unifying feature stands out as representing high autism risk[8].

A second less frequently used design method was serendipitously introduced by Chess[59] in her 1971 seminal article ‘Autism in Children with Congenital Rubella’. In the aftermath of the last rubella epidemic that took place in 1960s in the US, 243 children diagnosed with congenital rubella syndrome were placed under her care at the New York University Medical Centre. Of the 243 children, a psychiatric diagnosis of autism was reported in 10 children and a psychiatric diagnosis of atypical autism in a further eight children which represented 7.4% of the total group, consistent with cut-off estimates for high-scoring BAP social cognition trait prevalence in the general population. A comprehensive detailed description of the behavioural disturbances in two of the boys under Chess’s care diagnosed with autism was presented. The behavioural disturbances observed were indistinguishable from the very detailed behavioural disturbances of the 11 children described by Kanner[42].

The estimates for the prevalence of autism risk represented by the BAP highest scorers by various cut-offs in the general population of between 5% and 10% have been reported by Plomin’s group.The cut-offs can be applied to the variable diagnostic outcomes within studies based on the Chess design method.The design selects all individuals identified with a specific unfavourable pre-, peri- or neonatal event and reports the prevalence of autism within the group. The Rutter hypothesis would expect striking heterogeneity in outcomes and that the prevalence of autism within the studies would be consistent with and test the reliability of the general population autism risk estimates based on high BAP scoring cut-off ranges. Exclusionary criteria are studies with less than 20 participants, retrospective studies based on parental recall,studies that compared autism diagnosed samples only with various control groupsand studies that used autism screening tools only (Table 2).

Table 2

Autism prevalence identified with specific pre-, peri- and neonatal unfavourablefactors in the general population


Of the 17 studies listed only one, infantile spasms, was an outlier for autism risk with a 30% prevalence (6/20). The results of 16 of the 17 studies were predicted by the estimates of autism risk associated with a specific pre-, peri- or neonatal unfavourable factor in the general population of developmentally compromised or at-risk individuals of around 7% (the highest BAP scorers) and by the Rutter hypothesis.

Six of the syndromes listed (Table 2) have such a hugely massive environmental effect that preventative measures can or have been put in place. Prevention measures are in place for congenital rubella syndrome and thalidomide embryopathy with the development of an effective rubella vaccine and the ban on the use of thalidomide in obstetrics. Foetal alcohol syndrome, valproate acid syndrome, perinatal cocaine exposure syndrome and post institutional autistic syndrome are all preventable syndromes with a massive environmental effect and high autism risk.

The prevalence of autism in many genetically determined syndromes is frequently much greater than the approximate 7% that the Rutter hypothesis would predict. Moss and Howlin[76] have presented good evidence that in the genetically determined syndromes autism symptoms are associated with intellectual disability and cautioned against over interpreting the superficial similarities between autism and the behavioural phenotypes seen in most genetically determined syndromes. The authors also found that many genetically determined syndromes have their own unique pattern of superficial autism symptoms.

Twin studies in autism where one or both twins met diagnostic criteria for strictly defined or broadly defined autism have produced monozygotic twin concordance rates as high as 92% in broadly defined autism. Studies of general population twins have reported high BAP concordance rates and heritability estimates in general population twins, dependent on arbitrary cut-offs. Classical twin study design heritability estimates cannot control for the high rates of de novo mutations in autism therefore autism twin study heritability estimates are inflated. Common gene polymorphisms in candidate BAP genes are inherited therefore BAP concordance rates and heritability estimates may be more informative with respect to heritability estimates and general population autism risk. The implication within this model is that what the twin studies are reflecting may not be the heritability of autism at all but rather the concordance rate and heritability estimates of the independent BAP component part. The independent BAP component part can be characterised as the ‘missing heritability’ in autism[77].


The background BAP component part is a unifying feature that can be observed in G × G and G × E causal mechanisms that distinguishes autism cases from non-autism cases. Identifying unfavourable pre-, peri- and neonatal risk factors and environmental hazards associated with the severe developmental disorders (autism, intellectual disability, ADHD and schizophrenia) should be a high priority that might lead to more effective prevention strategies for these debilitating developmental conditions.

Author Contribution

All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.

Competing interests

None declared.

Conflict of interests

None declared.


All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.


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BAP candidate genes:genotype-phenotype expressions

22q11 COMT Self reported schizotypy traits Avramopoulos et al.14
22q11 COMT Anxiety and depression Hettama et al.15
22q11 COMT Obsessive compulsive disorder Liu et al.16
22q11 COMT Immune deficiencies McLean-Tooke et al.17
22q11 COMT Panic disorder Domschke et al.18
22q11 COMT Sensorimotor gating Stark et al.19
22q11 COMT Olfactory disorder Sobin20
22q11 COMT Hearing impairments Zarrchi et al.21
17q11–12 SLC6A4 Anti-social personality disorder Garcia et al.22
17q11–12 SLC6A4 Depression Brummett et al.23
17q11–12 SLC6A4 Depression and bulimia Mata & Gotlib24
17q11–12 SLC6A4 Borderline personality disorder Hankin et al.25
17q11–12 SLC6A4 First episode depression Bukh et al.26
17q11–12 SLC6A4 Obsessive compulsive disorder Denys et al.27
17Q11–12 SLC6A4 Irritable bowel syndrome Wang et al.28
17q11–12 SLC6A4 Rigid compulsive behaviours Sutcliffe et al.29
17q11–12 SLC6A4 Thermal pain thresholds Lindsted30
7q31 MET Immune function and gastrointestinal repair Randolph-Gips & Srinivasan13
7q31 MET Bipolar disorder Palo et al.31
7q31 MET Obsessive compulsive disorder Sakuri et al.32
7q31 MET Tourette’s syndrome (Tics) Patel et al.33
7q31 MET Tourette’s syndrome: depression, anxiety, phobic disorder, hostility and aggression Robertson34
7q35 CNTNAP2 FOXP2 Developmental language disorder Lennon et al.35
7q35 CNTNAP2 FOXP2 Obsessive compulsive disorder Verkerk et al.36
7q35 CNTNAP2 FOXP2 Variability in spoken language Alarcon et al.37
7q35 CNTNAP2 FOXP2 Diabetic nephropathy Conway et al.38
7q35 CNTNAP2 FOXP2 Auto-immune synaptic disorders Serratrice G & Serratirice J39
7q35 CNTNAP2 FOXP2 Dyslexia Peter et al.40
7q35 CNTNAP2 FOXP2 Selective mutism and social-anxiety related traits Stein et al.41

Autism prevalence identified with specific pre-, peri- and neonatal unfavourablefactors in the general population

Description ASD (%) Total diagnosed ASD Total in group Study design Author(s)
Congenital Rubella syndrome 7.4 18 243 Clinic Chess59
Thalidomide embryopathy 4.0 4 100 Clinic Stromland et al.60
Valproate acid syndrome 8.9 5 56 Clinic Rasalam et al.61
Fetal alcohol syndrome 8.3 2 24 Clinic Aronson et al.62
Unprovoked neonatal seizures 7.1 6 84 Population Saemundsen et al.63
Infantile spasms 30.0 6 20 Population Saemundsen et al.64
Newborn encephalopathy 5.0 12 239 Population Badawi et al.65
Premature birth 7.3 16 219 Population Johnson et al.66
Perinatal cocaine syndrome 11.4 8 70 Clinic Davis et al.67
Post institutional autistic syndrome* 9.8 22 224 Clinic Rutter et al.68 Hoksbergen et al.69
Severe paediatricconstipation 8.4 10 118 Clinic Pang & Croaker70
Neonatal arterial switch surgery 6.1 4 65 Clinic Neufeld et al.71
Congenital diaphragmatic hernia 7.3 3 41 Clinic Danzer et al.72
Renal disease/diabetes 5.6 3 53 Clinic Loirat et al.73
Low birth weight 4.9 31 623 Population Pinto-Martin et al.74
Cerebral palsy 8.1 39 476 Population Kirby et al.75
Totals 6.8 189 2745

*, pooled results of two post institutional autistic syndrome papers