Psychiatric Annals

CME Article 

Genetics of Autism Spectrum Disorder: An Update

Salma Malik, MD, MS, DFAACAP, DFAPA; Yasser Saeed Khan, MBBS, PGDPsych, MRCPsych, DCP; Robert Sahl, MD, DFAACAP, DFAPA; Khalid Elzamzamy, MD; Ahsan Nazeer, MD

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by a heterogeneous constellation of deficits in social communication and reciprocity along with restrictive, repetitive patterns of behavior. ASD is among the most heritable mental disorders with twin concordance rates ranging between 77% and 95% among monozygotic twins. Advances have been made in understanding the neurobiological mechanisms and genetic underpinnings of ASD. Over the past decades, studies have identified a role for both common and rare genetic variations contributing to autism. In this article, we review the genetics of ASD and highlight findings in the field. [Psychiatr Ann. 2019;49(3):109–114.]

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by a heterogeneous constellation of deficits in social communication and reciprocity along with restrictive, repetitive patterns of behavior. ASD is among the most heritable mental disorders with twin concordance rates ranging between 77% and 95% among monozygotic twins. Advances have been made in understanding the neurobiological mechanisms and genetic underpinnings of ASD. Over the past decades, studies have identified a role for both common and rare genetic variations contributing to autism. In this article, we review the genetics of ASD and highlight findings in the field. [Psychiatr Ann. 2019;49(3):109–114.]

The substantial increase in the prevalence of autism spectrum disorder (ASD) has received considerable attention, and significant research efforts are underway to understand the etiological basis of this disorder. It is known that the pathogenesis of ASD and other neurodevelopmental disorders involves an interaction between a multitude of genetic (nature) and environmental (nurture) risk factors. It is believed that the publication of the first twin study by Folstein and Rutter in 1977 that showed monozygotic (MZ) twins to be more concordant for autism (36%) as compared with dizygotic (DZ) twins (0%) was the starting point for further research in the genetics of ASD.1Table 1 lists some of the common terms that are used in genetics literature.

Genetics Terminology

Table 1.

Genetics Terminology

Epidemiology

Over the past two decades, the number of reported cases of autism has increased rapidly and the current prevalence rate is 1 in 59 children in the United States.2 This increase is partly due to improved awareness among health care professionals, changes in the diagnostic criteria, and increased number of children who are being diagnosed at an earlier age. It is important to note that there are differences in ASD prevalence between the sexes. Boys are estimated to be affected 4 to 5 times more than girls with the reported incidence now being 1 in 42 in boys and 1 in 189 in girls.3,4 This gender bias may be because of an ascertainment bias or the result of under-recognition of autism in girls.

Pathogenesis

The Diagnostic and Statistical Manual of Mental Disorders, fifth edition,5 uses one overarching classification, thus replacing distinct entities that included autistic disorder, Asperger's syndrome, Rett's disorder, childhood disintegrative disorder, and pervasive developmental disorder. ASD symptoms usually present during the early developmental period and are believed to be the result of environmental and genetic factors that affect brain development, especially the connectivity between the neurons.6–8 Other than the genetic factors, research has also identified the role of maternal infections during pregnancy,9 low birth weight,10 paternal age,11 multiple births,12 and shared environmental factors in twin pairs13 as some of the possible risk factors.

Genetic Factors

The cause of autism remains largely unknown; however, studies have identified more than 100 genes with ASD-risk mutations in 10% to 25% of the population.14 Most of the genes identified appear to affect the remodeling and dynamics of chromatin/actin (structural proteins) along with protein remodeling and synaptic functioning.15,16 A genetic basis of ASD is supported by twin concordance studies, the recurrence risk in families, and the coexistence with chromosomal disorders and rare genetic syndromes. Twin concordance is reported to be an estimated 77% to 95% among monozygotic twins compared to dizygotic twins (31%).17,18 However, there is a significant variability in the concordance estimates among studies, and, taken together, concordance appears to be around 45% to 16% among MZ and DZ twins, respectively.16 One study calculated relative recurrence risk (RRR) (Table 1) to access the heritability and familial aggregation of ASD. The RRR for ASD among monozygotic twins was estimated to be 153, for dizygotic twins 8.2, for full siblings 10.3, for maternal half siblings 3.3, for paternal half siblings 2.9, and for cousins 2.19

Regarding the gender difference in the prevalence of ASD, research findings are complex and there is no straight-forward relationship in the results. One theory is that the increased occurrence in males may be because of the X-linked transmission of ASD-risk genes.20

Overall, at least 103 known disease genes have been reported to be mutated, deleted, duplicated, or disrupted by a translocation breakpoint in people with ASD or autistic features. Furthermore, there have been 44 recurrent genomic disorders and chromosomal aneuploidies reported21 in this population. The earliest identified and recurrent chromosomal abnormalities are deletions of 22q11.2, 22q13.3, 2q37, and duplications of 15q11-13. Within the 15q11–15q13 locus, ubiquitin protein ligase E3A (UBE3A) and gamma-aminobutyric acid A receptor beta 3 are currently understood to be central. Other regions that are implicated include 5p15, 17p11, and Xp22.22

Single-gene mutations transmitted in autosomal dominant, autosomal recessive, and X-linked disorders have also been implicated in the pathogenesis of ASD. The most common single-gene mutation that is present in about 1% to 2% of cases in ASD is fragile X syndrome (FMR1). Similarly, tuberous sclerosis complex (TSC1, TSC2), Angelman's syndrome (UBE3A), Rett's disorder (MECP2), neurofibromatosis (NF1), and phosphatase and tensin homolog mutations are other monogenic disorders described in ASD. The rare mutations that have been identified in synaptic genes include NLGN3, NLGN4X, SHANK2, and SHANK3.22–25 The introduction of molecular cytogenetic testing, particularly chromosomal microarray analysis (CMA), has significantly increased the yield of genetic evaluations and is now preferred over conventional cytogenetics. When CMA can not be performed, a conventional chromosomal analysis is preferred to no testing at all.

Whole-genome microarray studies have identified submicroscopic deletions and duplications (copy number variation [CNV]) that are undetectable at the level of traditional cytogenetic analysis. These affect many loci and include de novo events in 1% of ASD cases. Most CNVs have incomplete penetrance for ASD and even the few with complete penetrance, except for truncating mutation in CHD8,26 do not lead to ASD in every person.

Epigenetic Theory

The term “epigenetics” was coined by British geneticist Conrad Waddington, who described it as “the interactions of genes with their environment, which bring the phenotype into being.”27 In other words, epigenetic changes are heritable changes in gene expression that occur early in the fetal development. These changes do not involve alterations in the primary DNA sequence but do affect the expression of other genes. Many environmental factors including toxins (lead, arsenic, dioxins, benzene, toluene), immunological irritants, nutritional deficiencies, and pharmaceuticals, that are associated with the risk of ASD exert their effects through physiological process within cells by changes in gene regulation.28 Research in the area of ASD has also revealed a mechanism of epigenetic influence through chromatin remodeling.29

Syndromic Autism

When ASD is expressed as a part of the behavioral manifestation of certain recognized genetic syndromes, it is then referred to as “syndromic,” as opposed to “idiopathic,” which does not have known genetic causes (Table 2).

Monogenic “Syndromic Autism” and Commonly Related Phenotypes

Table 2.

Monogenic “Syndromic Autism” and Commonly Related Phenotypes

People with syndromic ASD often have dysmorphic features characterized by the associated genetic syndrome and the male:female ratios are equal, unlike idiopathic autism, which occurs 4 to 5 times more frequently in males than in females.30 Single-gene disorders, including fragile X syndrome (mutations in FMR1), tuberous sclerosis complex (mutations in TSC1 and TSC2), Dup15q syndrome, deletions in the 16p11.2 region, Rett's disorder (mutation in MECP2), and neurofibromatosis (mutations in NF1), are detected in 3% to 5% of people with ASD, and are well-known for having an ASD phenotype as well as comorbid intellectual disabilities and epilepsy.31

Genetic Counseling

Despite the enthusiasm that surrounds discoveries of etiological factors of ASD and other neurodevelopmental disorders, major ethical and social challenges arise after such discoveries. Risk counseling for ASD, which was once reliant upon family history, empirical recurrence, and prevalence rates, is now shifting to incorporate genetic testing results. Genetic screening is usually helpful in cases where there is a direct correlation between phenotype and genotype, as in single-gene Mendelian disorders. However, in complex disorders such as autism, where the genetic profile is complex because of involvement of multiple genes, heterogeneity in the genetic makeup, genetic imprinting, and numerous gene-environment interactions, routine use of genetic testing, which is usually expensive, does not provide satisfactory yield. In addition, genetic variants are not associated with diseases every time they are detected. Nonetheless, having access to genetic testing is usually appreciated by families, especially when it is used to understand the degree of genetic susceptibility to a certain disease.

Genetic counseling lies at the interface between medicine and ethics. The process of genetic counseling is not just about sharing statistical probabilities, but rather it is a process of engagement with families in a manner that is supportive and sensitive to their personal, cultural, educational, and social backgrounds.32 Hoang et al.33 proposed a promising communication and counseling model to facilitate engagement with families relating to the complex nature of ASD and its etiological factors. Their model includes discussion topics, counseling tools, and the rationale for using each of these components of the model. Their counseling tools rely heavily on visual aids that may facilitate families' understanding. They propose discussing general genetic concepts, etiology of ASD, available genetic tests and their purpose, genetic results, and their significance as well as the psycho-social impact of the potential outcome of testing and diagnosing a family member with ASD.33

Finally, geneticists and genetic counselors are increasingly becoming an integral part of the multidisciplinary teams working with families and individuals with ASD. Clear paths of referrals to genetic counseling and communication among team members should be established to offer families the most evidence-based, culturally sensitive information that will assist them in their decision-making process.

Clinical Implications

The practice parameters of The American Academy of Child and Adolescent Psychiatry offer general recommendations regarding the need for genetic testing after the clinician has made the diagnosis of autism, especially in the presence of dysmorphic features or a family history of intellectual disability. Practice parameters recommend that children with ASD should have a Wood's lamp examination for signs of tuberous sclerosis, and genetic testing (G-banded karyotype, fragile X syndrome testing, or chromosomal microarray) as well.34 In a community sample of children with ASD, diagnostic yields were 2.5% for karyotype testing, 0.57% for fragile X syndrome testing, and 24% for chromosomal microarray.35 Chromosomal microarray has been recommended by medical geneticists as the standard of care for the initial evaluation of children with developmental disabilities and ASD.36

Schaefer et al.37 suggested to start the diagnostic process by making an accurate clinical diagnosis of ASD while paying special attention to dysmorphic features. Every person with ASD should be referred to a clinical geneticist for genetics evaluation. The clinical genetic evaluation of the patient should be individualized. Diagnosis should be confirmed using criteria and appropriate laborartory testing. For some patients, there are genetic conditions with ASD, but the association is not convincing, so an etiological independent evaluation with further testing could be done such as screening for folate-sensitive fragile sites or selected neurometabolic screening (mucopolysaccharides, amino acids, organic acids) along with referral to a metabolic specialist. Chromosomal microarray and DNA testing for fragile X syndrome for male patients can be considered. Genetic counseling can then be provided upon completion of the evaluation.37

Conclusion

Given the impact of ASD during the critical developmental period of children, it is imperative that the treating clinician understands all aspects of ASD including genetic contributions to the phenotypic presentation. During the last few decades, we have seen significant progress in our understanding of the genetics of ASD; however, many aspects of this complicated topic remain undiscovered. There is a need for further research to ascertain the specific biological pathways and risk candidate genes involved in the development of this disorder. Better understanding will help with an earlier diagnosis and therefore result in not only improvement in the quality of life and daily functioning of the people who are affected, but also allow for their effective inclusion and integration into the society.

References

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Genetics Terminology

Terms Definition
Chromosomal aneuploidy Having an abnormal number of chromosomes
Chromosomal microarray analysis A highly sensitive technology used to detect deletions and duplications in genetic information
Copy number variation The variation in number of copies of a particular gene in the genome of a person
Phenotypes Observable traits and characteristics that result from the interaction between one's genotype (nature) and environment (nurture)
Twin concordance study Investigate the probability that a pair of twins will both have a certain phenotypic trait if one of them has that trait
X-linked genes Genes on the X chromosome
Relative recurrence risk (for autism spectrum disorder) Risk of a diagnosis of autism in a sibling of a child who has autism compared to the sibling of a child who does not have autism

Monogenic “Syndromic Autism” and Commonly Related Phenotypes

Syndrome Mutations Phenotypes
Fragile X syndrome FMR1 Long face, large protruding ears, hypotonia, hyperextensible joints, intellectual disability, developmental delay, attention difficulties, autism spectrum disorder
Rett's disorder MECP2 Microcephaly, cognitive and motor impairment, developmental regression, epilepsy, stereotyped movements, severe autism spectrum disorder
Neurofibromatosis 1 NF1 Café au lait spots, neurofibromas, epilepsy, cognitive dysfunction, scoliosis, autism spectrum disorder
Tuberous sclerosis TSC1, TSC2 Multiorgan involvement, brain tumors, self-injurious behavior, obsessive-compulsive disorder, epilepsy, attention-deficit/hyperactivity disorder, autism spectrum disorder
Prader-Willi syndrome Del 15q11-q13 Characteristic facies, small hands and feet, hypogonadism, hyperphagia, severe obesity, hypopigmentation, mood and behavioral disturbance, autism spectrum disorder, obsessive-compulsive disorder
Angelman syndrome Dopamine-2 receptors and 5-hydroxytryptamine 2A receptors Strabismus, facial dysmorphism, prominent mandible, sleep disturbance, ataxia, attention issues, developmental delay, epilepsy, easily excitable, autism spectrum disorder
Smith-Magenis syndrome Del 17p11.2 Short stature, scoliosis, facial dysmorphism, reduced sensitivity to pain and temperature, self-injurious behavior, stereotyped behavior, sleep disturbances, autism spectrum disorder
Dup15q syndrome Dup15q11-q13, GABRB3 Facial dysmorphism, hypotonia, small stature, cognitive delay, behavioral problems, epilepsy, autism spectrum disorder
16p11.2 deletionsyndrome Del 16p11.2 Language delay, hypotonia, minor unusual facial features, overweight, epilepsy, learning difficulties, autism spectrum disorder
Authors

Salma Malik, MD, MS, DFAACAP, DFAPA, is a Training Director, and a Senior Attending, Child and Adolescent Psychiatry Division, Sidra Medicine. Yasser Saeed Khan, MBBS, PGDPsych, MRCPsych, DCP, is a Consultant Psychiatrist, and the Medical Lead, Child and Adolescent Mental Health Services, Hamad Medical Corporation. Robert Sahl, MD, DFAACAP, DFAPA, is a Division Chief, Institute of Living, Hartford Healthcare. Khalid Elzamzamy, MD, is a Psychiatry Resident, Hamad Medical Corporation. Ahsan Nazeer, MD, is the Division Chief, Child and Adolescent Psychiatry Division, Sidra Medicine.

Address correspondence to Salma Malik, MD, MS, DFAACAP, DFAPA, Sidra Medicine, Level 2nd Mezzanine, OPC, Office C2M 216, PO Box 26999, Al Luqta Street, Education City North Campus, Qatar Foundation, Doha, Qatar; email: smalik@sidra.org.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/00485713-20190212-01

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