“And autistic traits”, “with some autistic-type behaviours”, “some particular fixations on certain interests”, “autistic speech”.
These are expressions we frequently hear from parents during genetic counselling when they describe the clinical features of their young child, usually referred because of cognitive or developmental delay, ranging from mild to profound.
Sometimes, additional features are present: minor dysmorphic traits, such as downslanting palpebral fissures, or more pronounced congenital abnormalities. Sometimes there are neurological manifestations or other apparently unrelated clinical findings.
In our clinical experience, the association of developmental delay with autistic features and other clinical signs is surprisingly frequent.
As a result, a genetic consultation for developmental delay often involves discussing and better defining autistic traits — or an established diagnosis of autism spectrum disorder (ASD) — together with clinically important questions such as treatment, prognosis and reproductive risk.
Autistic features may be part of the behavioural phenotype of a much broader neurodevelopmental condition — and, in some children, they may represent one of several clues pointing towards an underlying genetic diagnosis.
→ If this situation feels familiar, start the diagnostic pathway here.
Clinical Clues
DELAYED MILESTONES
Delayed language, motor
or cognitive skills compared
with expected milestones.
AUTISTIC FEATURES
Restricted interests, repetitive behaviours or atypical social communication.
ASSOCIATED SIGNS
Intellectual disability, hypotonia, seizures, dysmorphic or congenital features.
GENETIC CLUE
When these features occur together, an underlying genetic disorder becomes more likely.
Understanding developmental delay and neurodevelopmental disorders
Developmental delay (DD) is a general term describing a delay in the acquisition of expected developmental milestones. It may involve motor development, sensory functions, cognitive development, language, or multiple developmental domains.
Neurodevelopmental disorders (NDDs) are a broader group of conditions affecting the development and functioning of the nervous system. They include intellectual disability (ID), autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and other conditions.
Therefore, while ASD is a neurodevelopmental disorder, it does not necessarily imply a broader developmental delay. A child with ASD, for example, may not have motor developmental delay or intellectual disability.
Autism spectrum disorder (ASD) is a clinical description, not an etiological diagnosis. This means that a child may fulfil the diagnostic criteria for ASD independently of its underlying cause — whether this reflects a complex multifactorial susceptibility or whether autistic features are part of an identifiable genetic disorder.
At the same time, the concept of autism itself has changed considerably. Research has progressively moved away from the idea of a single, well-defined form of “pure autism” towards the recognition that complexity and comorbidity are the norm. Rather than one autism with one biological explanation, ASD encompasses heterogeneous clinical presentations — and probably many different underlying biological conditions.
To make this distinction clearer, DD and NDD are terms built according to two different logics.
Developmental delay (DD) describes a phenotype — a clinical situation. It indicates that the acquisition of expected developmental milestones is delayed in one or more domains, including gross or fine motor skills, language, cognition and social development. As such, developmental delay may of course involve functions of the nervous system.
Neurodevelopmental disorder (NDD), instead, describes a category of disorders affecting the development and functioning of the nervous system. Autism spectrum disorder (ASD), intellectual disability (ID) and attention-deficit/hyperactivity disorder (ADHD), for example, are classified as neurodevelopmental disorders.
These examples may help clarify the difference:
- A child with ASD therefore has an NDD, but does not necessarily have developmental delay, particularly when intellectual and motor development are within the expected ranges.
- Conversely, an 18-month-old child who does not walk or speak within the expected developmental timeframe clearly shows developmental delay, but this finding alone does not necessarily establish a specific neurodevelopmental disorder.
- A child with ASD associated with intellectual disability and/or motor developmental delay may therefore present with both an NDD and DD.
| CLINICAL PRESENTATION | UNDERLYING CAUSE |
|---|---|
| ASD without developmental delay, intellectual disability or other major clinical features (formerly referred to as “pure autism”) | Strong genetic susceptibility has been demonstrated by family and twin studies. However, in most cases no single Mendelian or chromosomal cause can currently be identified, suggesting a predominantly complex and multifactorial genetic architecture. |
| ASD associated with developmental delay, intellectual disability and/or other major neurological or syndromic features | The probability of identifying an underlying genetic disorder increases substantially. In selected cohorts investigated by trio whole exome sequencing (WES), a monogenic or chromosomal cause may be identified in approximately 50% of cases. |
Why not all exomes have the same diagnostic value
→ Whole exome sequencing is often described in terms of genes covered, sequencing depth and technical performance. These parameters are important, but they do not entirely determine the diagnostic value of an exome.
In clinical practice, the probability of reaching a diagnosis also depends on how the genomic data are interpreted and integrated with the individual patient. Four elements are particularly important.
1. The experience of the interpreting geneticist
Some molecular diagnoses are relatively straightforward. A clearly pathogenic de novo variant in a gene strongly associated with the patient’s phenotype, for example, may be identified rapidly.
Other cases are considerably more complex. Several variants of uncertain significance may need to be evaluated one by one before the potentially causative variant emerges. Evidence from population databases, segregation, published cases, functional data and the patient’s phenotype must be considered together.
Variant classification itself is not entirely mechanical. ACMG criteria provide a structured framework, but individual lines of evidence may be adjusted by the geneticist based on their experience, assigning different levels of weight — from supporting to very strong — depending on the specific variant, the clinical context, or even previous individual knowledge of similar cases.
For this reason, WES is not simply a sequencing test: it is also an interpretative process.
2. The quality of the clinical information
An exome cannot be interpreted independently from the patient.
Detailed phenotypic information obtained during pre-test genetic counselling, together with previous medical records, imaging, neurological assessments and other clinical investigations, can substantially influence variant prioritization and interpretation.
In this respect, a thorough first clinical interview is essential. Particular attention should be paid to collecting all clinical signs and symptoms, including those that may initially appear secondary or unrelated to the main clinical problem. Sometimes, the apparently minor feature is precisely the one that helps connect the phenotype to a particular genetic condition. → Read our Clinical Insight: The Symptom You Didn’t Mention
Equally important, however, is the careful review of previous clinical documentation. Medical records may contain findings that parents do not remember, do not consider relevant, or simply do not mention during the consultation. Recovering these details may allow a more complete reconstruction of the patient’s clinical history and phenotype.
Both sources of information — the clinical interview and the previous medical documentation — are therefore complementary and essential. A more complete phenotype enables more precise variant filtering and, ultimately, a more accurate clinical interpretation of WES, trio WES or WGS data.
For this reason, Breda Genetics requires relevant previous clinical documentation to be provided before genomic interpretation begins.
3. Trio WES instead of singleton WES
Whenever possible, analysing the child together with both biological parents provides information that cannot be obtained from the child’s exome alone.
Trio WES makes the identification of de novo variants considerably more direct and immediately provides segregation information for recessive, X-linked and inherited dominant variants. Parental data may also become particularly useful when evaluating variants associated with reduced penetrance or variable expression.
The additional value of the trio therefore lies not simply in sequencing three individuals instead of one, but in interpreting the child’s genomic findings within their inheritance context.
4. The laboratory’s internal genomic data
The diagnostic performance of an exome also depends on the analytical infrastructure surrounding it.
This becomes particularly relevant for copy-number variant (CNV) analysis. WES data can be used not only to identify single nucleotide variants and small insertions or deletions, but also to detect genomic deletions and duplications, including alterations involving multiple exons within a gene (multiexonic deletions) or even a single exon, depending on the complexity of that particular genomic region and the sensitivity of the CNV-calling algorithm.
From this perspective, CNV analysis by exome sequencing can achieve a level of resolution well beyond that traditionally provided by array-CGH, reaching intragenic and, in selected regions, even single-exon alterations.
CNV calling relies partly on comparison of sequencing patterns across samples. A sufficiently large and technically consistent internal dataset can therefore contribute to the resolution and reliability of this analysis.
This is one reason why the diagnostic value of WES cannot be reduced simply to the number of genes sequenced or to sequencing depth alone.
Does motor delay matter more than language delay?
Language delay or atypical language development is very common in children with autism spectrum disorder and autistic features. For this reason, in a child already presenting with autistic features, language impairment alone may add relatively limited information when considering the possibility of an underlying genetic disorder.
Motor developmental delay may represent a different clinical clue.
When delayed walking, impaired motor development, hypotonia or other motor abnormalities accompany cognitive delay and autistic features, the phenotype extends beyond the predominantly cognitive, behavioural and communication domains. This broader developmental involvement raises a much stronger suspicion of an underlying genetic condition, including disorders associated with hypotonia, neuromuscular involvement or movement abnormalities.
Motor delay should therefore not be considered simply as another developmental milestone reached late. In the context of developmental delay with autistic features, it may represent an additional element supporting the indication for genomic investigation.
Once again, considering the overall costs and diagnostic benefits, the investigation generally points towards WES or, whenever possible, WES trio. WGS is certainly another valuable option, although WES trio and WGS offer different advantages and limitations depending on the clinical situation. → Read WES trio or WGS solo?
Does epilepsy increase the likelihood of a molecular diagnosis?
Epilepsy represents another important clinical clue when evaluating a child with developmental delay and autistic features.
Epilepsy is one of the most common comorbidities in individuals with ASD. Interestingly, a recent 2024 review identifies developmental delay/intellectual disability and an underlying genetic condition among the risk factors for epilepsy in individuals with ASD.
The relationship also works in the opposite direction from a diagnostic perspective: genetic testing becomes higher yield when epilepsy and ASD occur together. This makes the coexistence of developmental delay, autistic features and epilepsy particularly relevant when considering an underlying genetic disorder.
The characteristics of the epilepsy may also contribute to the interpretation of the overall phenotype: age at seizure onset, seizure type, EEG abnormalities, response to treatment and the presence of developmental regression can all provide valuable information when genomic variants are evaluated.
For this reason, the association of developmental delay, autistic features and epilepsy represents a strong indication for genomic testing. Considering the very large number of genes that may underlie these overlapping phenotypes, WES is generally more appropriate than testing individual genes or narrowly selected gene panels.
Whenever both biological parents are available, WES trio is particularly valuable, as it facilitates the identification and interpretation of de novo variants and immediately provides information on their inheritance. → Learn more about WES trio
Reference: Epilepsy and Autism Spectrum Disorders. Pediatric Clinics of North America, 2024. PMID: 38423718. DOI: 10.1016/j.pcl.2024.01.004.
When should Whole Genome Sequencing (WGS) be considered?
For a child with developmental delay and autistic features, WES trio should generally be preferred to WES performed on the child alone whenever both biological parents are available for testing. The simultaneous analysis of the child and both parents provides inheritance information from the beginning and considerably facilitates the interpretation of de novo, recessive and inherited variants.
When a WES has initially been performed on the child alone, parental testing can also be added subsequently, effectively extending the investigation to a family-based analysis when clarification of inheritance is required.
WGS may become particularly valuable in three clinical situations.
1. After a negative WES or WES trio
When WES — including subsequent parental analysis when appropriate — has failed to identify the cause, but the clinical suspicion of an underlying genetic disorder remains strong, Whole Genome Sequencing (WGS) represents a natural extension of the investigation.
It expands the analysis beyond the coding regions routinely investigated by WES and may identify variants in deep intronic and other non-coding regions, as well as genomic alterations that may be difficult to characterize through exome sequencing.
2. When the family chooses the broadest genomic investigation from the beginning
For families without significant budget constraints who wish to pursue the most comprehensive genomic investigation from the outset, WGS trio may be considered directly instead of WES trio.
This may be particularly attractive to parents interested not only in explaining their child’s current developmental condition, but also in the potential future use of genomic information for broader or predictive genomic assessment.
In this setting, however, diagnostic analysis and predictive genomic analysis should remain conceptually distinct, with appropriate counselling regarding the different types of findings that may emerge.
3. When biological parents are not available for testing
A different situation arises when parental samples cannot be obtained — for example, in an adopted child.
In these cases, the interpretative advantage normally provided by WES trio is unavailable. Starting directly with WGS may therefore be a reasonable alternative to WES solo, providing a broader genomic dataset from the outset and avoiding a stepwise strategy that cannot subsequently benefit from parental segregation analysis.
In most families in which both parents are available, our preferred starting point remains WES trio. WGS is not simply “a better exome”: its additional value depends on the clinical situation, family structure and objectives of the genomic investigation.
What happens when WES is negative?
A negative WES does not necessarily exclude an underlying genetic condition. Our knowledge of gene–disease associations continues to evolve, and variants that cannot be interpreted today may become diagnostically relevant in the future. For this reason, reanalysis of a negative exome after approximately 18–24 months may provide additional diagnostic findings, particularly as new disease genes and genotype–phenotype associations are continuously identified. When the clinical suspicion remains particularly strong, WGS may also represent the next diagnostic step, extending the investigation beyond the regions effectively explored by WES.
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