Autism Spectrum Disorders (ASD) Panel

Neurodevelopmental disorders are clinically diverse. Among them, autism spectrum disorder (ASD), intellectual disability (ID), and epilepsy have a high incidence of co-occurrence and significant overlap of genetic causes (Li et al. 2016. PubMed ID: 25849321; Jensen and Girirajan. 2017. PubMed ID: 29241461; Sztainberg and Zoghbi 2016. PubMed ID: 27786181).

ASD is characterized by varying degrees of social impairment, communication ability, propensity for repetitive behavior(s), and restricted interests (Levy et al. 2009. PubMed ID: 19819542). Incidence of ASD is approximately 1 in 54 individuals with a male-to-female ratio of 4:1 (Maenner et al. 2020. PubMed ID: 32214087). ASD symptoms usually present by age 3, and diagnosis is based on the degree and severity of symptoms and behaviors (McPartland et al. 2016). Comorbidities are observed in more than 70% of cases, and include ID, epilepsy, language deficits, and gastrointestinal problems (Sztainberg and Zoghbi. 2016. PubMed ID: 27786181). Co-occurring ASD and ID has a similar male-to-female prevalence ratio of 4:1 (Christensen et al. 2016. PubMed ID: 27031587). Furthermore, neurodevelopmental phenotypes are frequently associated with other medical conditions (for example cardiac defects, renal anomalies) prompting changes in clinical management of the individual (Vorstman et al. 2017 PubMed ID: 28260791).

ASDs are subdivided into idiopathic and syndromic forms. Syndromic ASD patients present with additional phenotypes or dysmorphic features and represent ~5% of all ASD cases (Casanova et al. 2016. PubMed ID: 26985359). In most cases, multiple genetic and environmental factors play a role in the development of ASD. Depending on the gene, variants may only be a risk factor for ASD, have incomplete penetrance, and/or be insufficient to cause ASD on their own (Hoang et al. 2017. PubMed ID: 28803755).

The heritability of ASD is multifactorial and reportedly ranges between 50-90% (Larsen et al. 2016. PubMed ID: 27790361; Lichtenstein et al. 2010. PubMed ID: 20686188). ASD concordance is as high as 70% in monozygotic twins. Familial recurrence rates are 7% if the first affected child is female and 4% if first affected child is male (Schaefer and Mendelsohn. 2008. PubMed ID: 18197051). Interestingly, ~69% of affected siblings carry different rare, penetrant variants in multiplex families, while shared de novo events have been reported in approximately 20% of sibling pairs (Yuen et al. 2015. PubMed ID: 25621899).

Chromosomal abnormalities (Fragile X syndrome, translocations, recurrent microdeletions/duplications, copy number variants) and pathogenic sequence variants, familial and de novo, can explain ~30% of ASD cases. Low-level mosaicism and balanced translocation variants are causative in less than 1% of ASD cases. Monogenic causes of ASD are reported in 10-20% of individuals, however no single gene accounts for more than 1% of all ASD cases (Ilyas et al. 2020. PubMed ID: 31984132; Wang et al. 2020. PubMed ID: 32429945; Miller et al. 2010. PubMed ID: 20466091; Rylaarsdam and Guemez-Gamboa. 2019. PubMed ID: 31481879; Vissers et al. 2016. PubMed ID: 26503795; Bourgeron. 2015. PubMed ID: 26289574). For ASD, de novo missense and likely gene disrupting variants are 15% and 75% more frequent, respectively in patients than unaffected controls (Iossifov et al. 2014. PubMed ID: 25363768). Hence, trio testing (whenever possible) is considered the most powerful approach for genetic diagnosis of ASD (Lee et al. 2014. PubMed ID: 25326637; Wright et al. 2015. PubMed ID: 25529582).

This test includes genes that through literature, OMIM, and HGMD searches have a clear association with ASD phenotypes. See individual gene summaries for information about the molecular biology of gene products and spectra of pathogenic variants.

CMA and FMR1 CGG-repeat expansion testing have a reported diagnostic yield of up to 15% for individuals with ASD and/or developmental delay phenotypes (Schaefer and Mendelsohn. 2013. PubMed ID: 23519317; Woodbury-Smith and Scherer. 2018. PubMed ID: 29574884; Vasudevan and Suri. 2017. PubMed ID: 29196358; Bass and Skuse. 2018. PubMed ID: 30138136). Combined genetic approaches (karyotype, CMA, and exome analysis) have identified a genetic diagnosis in 25-30% of ASD cases (Bourgeron. 2015. PubMed ID: 26289574; Bowling et al. 2017; PubMed ID: 28554332). 

Trio-based studies achieve the highest diagnostic rates for developmental phenotypes due to their ability to phase compound heterozygous variants and identify de novo events (30-40%, Lee et al. 2014. PubMed ID: 25326637; Fitzgerald. 2015. PubMed ID: 25533962; Wright et al. 2015. PubMed ID: 25529582; Retterer et al. 2016. PubMed ID: 26633542). Therefore, when possible, parental testing is recommended to maximize clinical sensitivity of this panel and inform variant interpretation.

This test will detect large deletions and insertions (Copy Number Variants, CNVs) as well as smaller sequence variants (nucleotide substitutions and small deletions and insertions (SNVs)) with high analytical sensitivity. Detection of trinucleotide repeat expansions (as seen in Fragile X Syndrome, for example) requires an alternative test. FMR1 CGG-repeat expansion is NOT part of this panel and can be ordered using Test Code #558.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.1% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).