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*Corresponding author Email: rajensen088@aol.com
Introduction
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 (
Conclusion
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:
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.
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
 |
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].
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
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).
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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.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
None declared.
None declared.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
BAP candidate genes:genotype-phenotype expressions
| 22q11 |
Self reported schizotypy traits | Avramopoulos et al. |
| 22q11 |
Anxiety and depression | Hettama et al. |
| 22q11 |
Obsessive compulsive disorder | Liu et al. |
| 22q11 |
Immune deficiencies | McLean-Tooke et al. |
| 22q11 |
Panic disorder | Domschke et al. |
| 22q11 |
Sensorimotor gating | Stark et al. |
| 22q11 |
Olfactory disorder | Sobin |
| 22q11 |
Hearing impairments | Zarrchi et al. |
| 17q11–12 |
Anti-social personality disorder | Garcia et al. |
| 17q11–12 |
Depression | Brummett et al. |
| 17q11–12 |
Depression and bulimia | Mata & Gotlib |
| 17q11–12 |
Borderline personality disorder | Hankin et al. |
| 17q11–12 |
First episode depression | Bukh et al. |
| 17q11–12 |
Obsessive compulsive disorder | Denys et al. |
| 17Q11–12 |
Irritable bowel syndrome | Wang et al. |
| 17q11–12 |
Rigid compulsive behaviours | Sutcliffe et al. |
| 17q11–12 |
Thermal pain thresholds | Lindsted |
| 7q31 |
Immune function and gastrointestinal repair | Randolph-Gips & Srinivasan |
| 7q31 |
Bipolar disorder | Palo et al. |
| 7q31 |
Obsessive compulsive disorder | Sakuri et al. |
| 7q31 |
Tourette’s syndrome (Tics) | Patel et al. |
| 7q31 |
Tourette’s syndrome: depression, anxiety, phobic disorder, hostility and aggression | Robertson |
| 7q35 |
Developmental language disorder | Lennon et al. |
| 7q35 |
Obsessive compulsive disorder | Verkerk et al. |
| 7q35 |
Variability in spoken language | Alarcon et al. |
| 7q35 |
Diabetic nephropathy | Conway et al. |
| 7q35 |
Auto-immune synaptic disorders | Serratrice G & Serratirice J |
| 7q35 |
Dyslexia | Peter et al. |
| 7q35 |
Selective mutism and social-anxiety related traits | Stein et al. |
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 | Chess |
| Thalidomide embryopathy | 4.0 | 4 | 100 | Clinic | Stromland et al. |
| Valproate acid syndrome | 8.9 | 5 | 56 | Clinic | Rasalam et al. |
| Fetal alcohol syndrome | 8.3 | 2 | 24 | Clinic | Aronson et al. |
| Unprovoked neonatal seizures | 7.1 | 6 | 84 | Population | Saemundsen et al. |
| Infantile spasms | 30.0 | 6 | 20 | Population | Saemundsen et al. |
| Newborn encephalopathy | 5.0 | 12 | 239 | Population | Badawi et al. |
| Premature birth | 7.3 | 16 | 219 | Population | Johnson et al. |
| Perinatal cocaine syndrome | 11.4 | 8 | 70 | Clinic | Davis et al. |
| Post institutional autistic syndrome* | 9.8 | 22 | 224 | Clinic | Rutter et al. |
| Severe paediatricconstipation | 8.4 | 10 | 118 | Clinic | Pang & Croaker |
| Neonatal arterial switch surgery | 6.1 | 4 | 65 | Clinic | Neufeld et al. |
| Congenital diaphragmatic hernia | 7.3 | 3 | 41 | Clinic | Danzer et al. |
| Renal disease/diabetes | 5.6 | 3 | 53 | Clinic | Loirat et al. |
| Low birth weight | 4.9 | 31 | 623 | Population | Pinto-Martin et al. |
| Cerebral palsy | 8.1 | 39 | 476 | Population | Kirby et al. |
| Totals | 6.8 | 189 | 2745 |
*, pooled results of two post institutional autistic syndrome papers
