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Conditions

Autism spectrum disorder

Autism spectrum disorder describes a group of conditions in which an individual experiences difficulties with social communication and may show restricted and repetitive patterns of behaviour, such as unusual movements (motor mannerisms), insistence on routine, sensory sensitivity and obsessive or unusual interests.

Overview

Autistic characteristics are usually noticed in the preschool years. There are a range of early signs that parents might report. These may include a child using less eye contact, or a delay or difference in speech and language development and communication.

However, when children have more subtle features and/or are intellectually able, the characteristics may not be recognised until they are older.

Clinical features

Presenting features of autism spectrum disorder (ASD) can vary depending on age, cognitive ability, gender and co-existing medical or neurodevelopmental conditions. Latest studies indicate a 3:1 male to female ratio in the prevalence of autism. A list of frequently observed clinical features, and some examples of how they can present, is provided below.

  • Reduced social and emotional reciprocity:
    • lack of reciprocal communication needed to engage in to-and-fro social conversation;
    • failure to initiative or respond to social interaction; and
    • reduced sharing of interests and/or emotions.
  • Deficits in non-verbal communication:
    • limited use of eye contact;
    • limited use of gesture; and
    • limited facial expression.
  • Impaired reciprocal social interaction:
    • difficulties understanding and developing relationships; and
    • lack of interest in peers.
  • Restricted and repetitive behaviours and/or interests:
    • repetitive movements (for example, hand flapping);
    • repetitive speech;
    • highly restricted or fixated interests;
    • reduced flexibility – difficulty managing transitions or change of routine; and
    • hyper- or hypo-reactivity to sensory stimuli.
  • Associated neurodevelopmental and other features:
    • intellectual disability (mild to severe);
    • global developmental delay;
    • specific learning disability;
    • developmental coordination disorder;
    • special talents, for example in arithmetic or art;
    • attention deficit hyperactivity disorder (ADHD);
    • psychiatric conditions, including anxiety, depression, obsessive-compulsive disorder and eating disorders;
    • sleep disturbance;
    • epilepsy; and
    • subtly distinctive appearance.

Genomics

The genetics of ASD are complex, with polygenic inheritance and potential environmental factors contributing to phenotypic variation.

There is evidence that certain copy number variants (CNVs) are overrepresented in individuals with autism. These include 1q21.1 microdeletion or duplication, 3q29 microdeletion, 7q11.23 duplication, 16p11.2 microdeletion, 15q11.2–q13 duplication, and 22q11.2 deletion or duplication.

There are many genetic syndromes in which ASD, or autistic traits, are more likely to be observed. When an underlying syndromic cause is present then individuals are likely to demonstrate additional features, such as a distinctive appearance, congenital anomalies, aberrant growth patterns (tall or short stature, macro- or microcephaly), motor impairment, seizures or more significant intellectual disability.

It is important to note that individuals with a syndromic diagnosis and features of autism should be assessed for autism. This is important as it leads to useful information and support.

For information about testing for ASD, see Presentation: Child with a suspected autistic spectrum disorder and Presentation: Child with developmental delay or intellectual disability.

Syndromic ASD

The main genetic conditions of which ASD is a known feature, together with their associated gene(s) or CNVs, are listed below.

  • 16p11.2 microdeletion syndrome: This is one of the most common known genetic causes of ASD typically presenting with speech and language impairment, motor coordination difficulties, a tendency to become overweight or obese and seizures.
  • 15q11–q13 duplication syndrome: This is a highly variable condition characterised by central hypotonia, global developmental delay (predominantly motor), variable intellectual disability and seizures (including infantile spasms).
  • 22q11.2 deletion syndrome (also known as DiGeorge syndrome): This is a highly variable multisystem condition associated with learning, behavioural and psychiatric difficulties, as well as a list of features that are together sometimes abbreviated to CATCH22: cardiac defects, abnormal facies, thymic hypoplasia, cleft palate and hypocalcaemia.
  • Fragile X syndrome: This is an X-linked condition presenting in early childhood with intellectual disability, characteristic dysmorphic features and ASD (50%–70% of cases). It is the most common inherited cause of intellectual disability in boys.
  • Down syndrome (trisomy 21): A multisystem condition characterised by intellectual disability, a higher chance of congenital malformations and other health problems, and recognisable physical features.
  • Tuberous sclerosis complex (TSC1/TSC2): This is a highly variable multisystem condition characterised by the widespread growth of benign tumours and often associated with seizures and neurodevelopmental conditions (ASD in 20%–65% of cases).
  • Neurofibromatosis type 1 (NF1): This is a neurocutaneous condition characterised by multiple neurofibromas, café-au-lait macules, freckling in atypical locations and neurodevelopmental features, including ASD. There is an increased chance of malignant tumours.
  • Noonan syndrome (PTPN11/SOS1/RIT1/KRAS/NRAS/HRAS/SHOC2): This is a condition caused by variants in several identified genes, characterised by early feeding difficulties, short stature, developmental delay, congenital heart disease (typically pulmonary stenosis) and a distinctive craniofacial appearance.
  • Rett syndrome (MECP2/FOXG1/CDKL5): This is a progressive neurodevelopmental condition occurring almost exclusively in females. It is characterised by developmental regression, repetitive hand movements, seizures and growth plateau.
  • Angelman syndrome (disruption of genes at 15q11.2–q13, notably UBE3A): This is an imprinting condition characterised by significant learning disabilities, seizures (with a characteristic electroencephalogram (EEG) pattern), ataxic gait and a happy, excitable demeanour.
  • Prader-Willi syndrome (disruption of genes at 15q11.2-q13, notably SNRPN). This is an imprinting condition characterised by neonatal hypotonia and poor feeding, following by childhood hyperphagia, obesity and intellectual disability.
  • Cohen syndrome (VPS13B): This is a multisystem developmental condition characterised by microcephaly, distinctive physical features, hypotonia, intellectual disability, truncal obesity and retinal dystrophy.
  • Cornelia de Lange syndrome (NIPBL, SMC1A, SMC3, RAD21, HDAC8): This is a variable multisystem malformation syndrome characterised by distinctive facial features, limb anomalies, pre- and postnatal growth restriction, microcephaly and intellectual disability.
  • CHARGE syndrome (CHD7): This is a rare multisystem condition of early embryonic onset, characterised by coloboma and cranial nerve anomalies, heart anomalies, atresia of the choanae, restriction of growth, genital underdevelopment and ear anomalies. Developmental and intellectual difficulties are highly variable.
  • Joubert syndrome (over 40 causative genes): This is a variable primary ciliopathy, characterised by a combination of structural brain anomalies (classically the molar tooth sign), characteristic facial appearance, hypotonia, developmental delay, difficulty moving the eyes to look at an object (oculomotor apraxia) and, in some individuals, dysregulated breathing and kidney cysts. Intellectual and behavioural difficulties are common and may be severe.
  • Smith-Lemli-Opitz syndrome (DHCR7): This is a variable multisystem condition characterised by a distinctive appearance, microcephaly, growth restriction, intellectual disability and congenital anomalies (such as cleft palate, polydactyly, two/three toe syndactyly and ambiguous genitalia).
  • Timothy syndrome (CACNA1C): This is an ultra-rare multisystem condition, characterised by prolonged QT interval, syndactyly and neurodevelopmental delay.
  • PTEN hamartoma tumour syndrome (PTEN): This is a spectrum of multisystem conditions characterised by multiple hamartomas, a predisposition to benign and malignant tumours, macrocephaly, distinctive mucocutaneous changes and, occasionally, features of ASD (examples of this include macrocephaly/autism syndrome and Cowden and Bannayan-Riley-Ruvalcaba syndrome).

Non-syndromic ASD

  • Non-syndromic ASD is a multifactorial group of conditions with a strong polygenic component.
  • The pattern of genetic changes, combined with environmental risk factors, determines an individual’s overall chance of developing ASD.
  • The genetic architecture is complex, and variations in over 100 genes (for example ADNP, ARID1B, ANK2 and SCN2A), together with neuro-susceptibility loci, are strongly associated with ASD.
  • Associated genetic changes can be inherited or can occur de novo (seen more frequently in association with advanced paternal age). They include chromosomal changes, CNVs, small insertions and deletions (indels), and single nucleotide variants (SNVs).
  • Microarray testing is useful in assessing for chromosomal changes and CNVs, while broader sequencing approaches (whole exome sequencing and whole genome sequencing) have a low yield in isolated, non-syndromic ASDs and are more useful for investigating those with additional features suggestive of a unifying genetic diagnosis.

Types of genomic variant associated with non-syndromic ASD

  • Common inherited genomic variants:
    • commonly seen in the general population;
    • account for up to 40% of the genetic architecture of ASD; and
    • individually have a small effect, but the collective effects are additive.
  • Rare inherited genomic variants:
    • account for a small proportion of cases of ASD;
    • have a larger effect size than individual common variants; and
    • are more common where there are multiple affected individuals in the family.
  • De novo coding variants:
    • CNVs have a larger effect size and account for up to 5% of cases of ASD; many are proposed to affect the expression of important synaptic genes, for example NRXN1 and SYNGAP1.
    • SNVs and structural variants, including translocations, are also implicated with a range of effect sizes.
  • Non-coding variants:
    • There is emerging evidence that variants in non-coding regions may also be implicated in ASD.

Diagnosis

Genomic testing should be considered for individuals presenting with unexplained features of ASD, alongside:

  • moderate to profound intellectual disability;
  • motor developmental delay;
  • other medical problems, such as seizures or congenital heart disease;
  • unusual growth patterns, such as growth restriction, overgrowth or asymmetric growth;
  • microcephaly or macrocephaly;
  • distinctive facial features; and/or
  • a family history of learning disability (particularly if it followed an X-linked pattern), or of multiple miscarriages.

Patients with isolated autism or mild intellectual disability are no longer eligible for genomic testing. This is because the chance of finding an underlying genetic condition in this group is very low. For more information about testing please see Presentation: Child with suspected autism spectrum disorder.

Inheritance and genomic counselling

  • Non-syndromic ASD follows a multifactorial mode of inheritance. It appears to segregate in families, but with no clear pattern.
  • Heritability is estimated to range between 40%–80%. Incomplete penetrance and variability in expression are frequently observed in families. It is estimated that parents who have a child with non-syndromic ASD have a 2%–18% chance of having a second affected child.

For individuals found to have an underlying syndromic condition, the sibling and offspring chance of inheriting that condition will be dictated by the inheritance pattern of the specific condition. Many syndromic causes of autism are variable in presentation. Other affected family members may or may not meet the full diagnostic criteria for ASD. If an underlying genetic cause is identified there may be reproductive and wider familial implications that must be considered.

Management

Management of individuals with ASD is complex. It should focus on supporting communication and education, as well as on managing coexisting conditions. The multidisciplinary team may include primary care, education, paediatrics, child and adolescent mental health services (CAMHS), and other allied health professionals.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 21/02/2025
  • Next review due: 21/02/2027
  • Authors: Dr Danielle Bogue
  • Reviewers: Dr Lianne Gompertz, Dr Ellie Hay, Dr Joanna Kennedy