Overview
Autism spectrum disorders (ASD) are characterized by a high degree of heritability, with modern genetic methods being able to identify a clear genetic cause in 20-25% of cases. De novo copy number variations (CNVs) are found in approximately 20% of those affected. The American College of Medical Genetics recommends a step-by-step diagnostic approach. Since over 1000 genes may be involved in the development of ASD, extended diagnostics using exome sequencing can lead to more precise diagnoses.
Scientific background
Autism spectrum disorders (ASD) are among the neuropsychiatric diseases with the greatest heritability, as shown by high concordance rates of about 70% in monozygotic twins in early twin studies. Based on this, the empirical risk of recurrence for siblings of children with ASD is between 5 and 20%, which is significantly higher than for other multifactorial disorders. ASD is clinically and genetically heterogeneous; the most common comorbidities are developmental disorders or reduced intelligence (approximately 70%), language disorders (approximately 30%), or epilepsy.
Cause
It is now thought that numerous genes, probably more than 1,000, may be involved in the development of ASD, although it is not yet clear to what extent individual variants influence the severity in individual cases.
It is currently assumed that modern genetic testing methods can identify a genetic cause for around 20 to 25% of autism spectrum disorders (Baker et al., 2015). Approximately 20% carry de novo generated CNV (copy number variation), which are detected by chromosomal microarrays (CMA). Monogenic causes are found in 3-5% of cases, mostly for syndromes caused by pathogenic variants in single genes that show ASD as a partial symptom.
Diagnosis
Diagnosis using whole exome sequencing (WES) can lead to a diagnosis in individual cases and thus to more accurate statements about the prognosis and the risk of recurrence.
The American College of Medical Genetics (ACMG) (Schaefer et al., 2013) recommends performing chromosomal microarray before genetic testing for patients with ASD in whom clinical examination does not indicate a specific genetic syndrome. If the chromosomal microarray analysis is normal, the MECP2 gene (Rett syndrome) should be examined in girls, the FMR1 gene (fragile X syndrome) in boys, or the PTEN gene (Bannayan-Riley-Ruvalcaba syndrome) if macrocephaly is present.
References
Grove et al. 2019, Nat Genet 51:431 / Yuen et al. 2017, Nat Neurosci 20:602 / Baker et al. 2015, Pediatr Clin N Am 62:607 / Schaefer et al. 2013, Gen Med 15(5):399
See also: Charge syndrome, Rubinstein-Taybi syndrome, Pitt-Hopkins syndrome, Sotos syndrome, and Weaver syndrome.
