Genetics and autism: inheritance, genetic tests and recurrence risk

Rare and common variants

The review describes two groups of gene variants that contribute to the risk of autism: rare variants with a large effect, often new mutations (de novo), and common variants with a small effect. ^[1] Rare variants are more common in people with additional intellectual disability but occur across the whole spectrum. ^[1] The same variants can be associated with different presentations or also with other diagnoses such as ADHD or schizophrenia (pleiotropy); autism is thus very heterogeneous at the molecular level too. ^[1] How the findings on heritability and twin studies fit in is here: Causes of autism.

Why genetics is no verdict on individuals

Carriers of a particular variant and their relatives can remain healthy, show the same picture with a different severity or have an entirely different picture. ^[1] Besides individual variants, the whole genetic background and chance factors play a role. ^[1] Genetics therefore explains risk, not individual “blame” or prediction. For some genetic conditions that can occur together with autism, such as fragile X syndrome, this is clarified medically: Common co-occurring conditions in autism. ^[2]

Recurrence risk in siblings

When families make decisions on family planning or worry about siblings, recurrence risks from family studies were traditionally used. According to the review, the estimates vary greatly between studies and countries and depend on which families were studied. ^[1] Typically, rates between 10 and 15 per cent were reported for siblings of people with autism; the risk is higher if the person affected is female, and higher in male than in female siblings. If two siblings are already affected, about 30 to 50 per cent were reported. ^[1] These figures are averages from studies; they are not tailored to the individual family. ^[1]

Genetic tests: benefits and limits

• Common variants: According to the review, there is currently no clinical reason for testing, because their predictive value is limited. ^[1]
• Rare variants and syndromes: Tests for certain syndromes such as fragile X syndrome and tuberous sclerosis have long been part of clarification when such syndromes are suspected; chromosomal microarray tests are available in many countries as a first genetic test. Possible benefits include a more precisely tailored recurrence risk, access to self-help groups, a better understanding of how the autism arose, and earlier recognition and treatment of associated medical conditions. ^[1]
• Recommendations differ: In the USA it was recommended that all people with an autism diagnosis be tested for copy number variants by chromosomal microarray; in other countries, including Great Britain, routine genetic testing is recommended only with additional intellectual disability or noticeable physical features. ^[1] How this is regulated in Germany is not described in this article.
• Difficulties: Findings are hard to interpret (variable expression); it is not always clear whether a known variant is causal in the individual person. Negative consequences of a test also have to be considered, such as disappointment at a negative finding, guilt, shame or fears as well as possible effects on insurance and life planning. ^[1] For autism, according to the review there is so far no evidence of the cost-effectiveness of genetic tests. ^[1]
• Assessment of the authors: They regard referral for human-genetic examination and counselling as appropriate in autism with intellectual disability or a complex picture (additional physical features, medical condition); this assessment could change quickly and depend on context. ^[1]

Limits and open questions

• State of the source: The review dates from 2020 and was published in 2021; the field is developing quickly. ^[1]
• Open: Whether the gene findings yield shared biological pathways that could be treated is still unclear according to the paper. ^[1]
• Read figures with caution: Recurrence rates depend on the study and are only a rough orientation for an individual family. ^[1]
• Germany: Recommendations and services in Germany (human-genetic counselling, cost coverage) are not presented here.

What else you should know

• Advice: Questions about genetic tests and the risk for siblings belong with human-genetic counselling; the paediatric practice or assessment service can refer you there. This is an orientation for action from the editorial team, not derived from the review.
• Vaccinations and parenting are not a cause according to the studies: Causes of autism and Do vaccinations cause autism?.
• How to put studies in context: How good is a study?

Sources and literature

1. Thapar A, Rutter M. Genetic advances in autism. Journal of Autism and Developmental Disorders 2021;51(12):4321–4332. https://doi.org/10.1007/s10803-020-04685-z (PMC8531042) – Review article
2. Höhne E, Kamp-Becker I. Diagnostik der Autismus-Spektrum-Störung. Pädiatrie (Rosenfluh) 2024;(4+5):27–32. – Expert overview (in German) (genetische Begleiterkrankungen, zum Beispiel Fragiles-X-Syndrom)