Intellectual Disability, Epilepsy, and Autism (IDEA) Panel

Summary and Pricing

Test Requisition Form

Test Method

Exome Sequencing with CNV Detection
Test Type Test Code Total Price STAT
Family - Trio (IDEA panel of patient + 2 additional family members) 11865 $2290 Add to Order
Patient Plus (IDEA panel of patient + targeted variant testing of parents. Both parents required) 5201 $1790 Add to Order
Family - Duo (IDEA panel of patient + 1 additional family member) 11864 $2090 Add to Order
Patient Only (IDEA panel of patient) 5045 $1690 Add to Order
Genes Panel CPT Code Gene CPT Codes
Genes x(2285) 81470 81161(x1), 81175(x1), 81185(x1), 81189(x1), 81236(x1), 81302(x1), 81304(x1), 81307(x1), 81321(x1), 81323(x1), 81403(x9), 81404(x41), 81405(x74), 81406(x91), 81407(x20), 81408(x11), 81479(x4314)

For a full list of genes click here.

Pricing Comment

We are happy to accommodate requests for single genes or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered on our PGxome Custom Panel.

Sequencing cost to additional family members beyond trio: $390 (no report).

If report is needed for any additional family members, add $490.

The price to reflex to PGxome is $390.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Turnaround Time

30 days average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Neurodevelopmental disorders are clinically diverse. Among them, intellectual disability (ID), epilepsy, and autism spectrum disorder (ASD) 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). 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). The Intellectual Disability, Epilepsy, and Autism (IDEA) Panel analyzes over 2,000 genes associated with these neurological phenotypes.

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). 

ID refers to significant impairment of cognitive and adaptive development (IQ<70) due to abnormalities of brain structure and/or function (American Association of Intellectual and Developmental Disabilities, AAIDD). ID is not a single entity, but rather a general symptom of neurologic dysfunction that is diagnosed in ~1-3% of the worldwide population (Kaufman et al. 2010. PubMed ID: 21124998; Vissers et al. 2016. PubMed ID: 26503795; Wang et al. 2020 PubMed ID: 3249945). Genetic and non-genetic factors (for example, congenital infections, prenatal exposures, trauma) all contribute to the etiology of ID (Sabo et al. 2020. PubMed ID: 32767738). Approximately 30% more males are diagnosed with ID than females, however this ratio decreases as IQ decreases (American Psychiatric Association. 2000; Kaufman et al. 2010. PubMed ID: 21124998). Co-occurring ASD and ID has a similar male-to-female prevalence ratio of 4:1 (Christensen et al. 2016. PubMed ID: 27031587).

Epilepsy is characterized by abnormal activity in the brain resulting in recurrent unprovoked seizures (https://www.ilae.org/). Seizures are classified based on their onset: focal, generalized, and unknown (Fisher et al. 2017. PubMed ID: 28276064). Epilepsy classification follows similar categories: focal, generalized, combined generalized and focal, and unknown (Scheffer et al. 2017. PubMed ID: 28276062). The third level of diagnosis is defining an epilepsy syndrome. Epilepsy occurs among individuals that are otherwise typically-functioning and as a comorbidity in complex neurological diseases. Among patients with epilepsy, there is great variation in the age of onset, type of seizures, developmental outcome, EEG and image findings, response to medication, and associated comorbidities. The incidence of epilepsy is approximately 1 in 2,000 (Ngugi et al. 2011. PubMed ID: 21893672).

Genetics

ASD, ID and epilepsy are caused by diverse and overlapping etiologies, collectively involving thousands of genes. As a result, all forms of Mendelian inheritance have been documented among these disorders. 

Heritability reportedly ranges between 50-90% and 15-50% for ASD and ID, respectively (Larsen et al. 2016. PubMed ID: 27790361; Lichtenstein et al. 2010. PubMed ID: 20686188; Karam et al. 2015. PubMed ID: 25728503). 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). For ID, genetic factors are identified in less than half of cases (Vissers et al. 2016. PubMed ID: 26503795; Milani et al. 2015. PubMed ID: 27617122; Ilyas et al. 2020. PubMed ID: 31984132).

Chromosomal abnormalities (Fragile X syndrome, translocations, recurrent microdeletions/duplications, copy number variants) and pathogenic sequence variants, familial and de novo, can explain ~30% and ~40% of ASD and ID cases, respectively. Low-level mosaicism and balanced translocation variants are causative in less than 1% of ASD and ID 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 in patients than unaffected controls, respectively (Iossifov et al. 2014. PubMed ID: 25363768). Hence, trio testing (whenever possible) is considered the most powerful approach for genetic diagnosis of ASD and ID (Lee et al. 2014. PubMed ID: 25326637; Wright et al. 2015. PubMed ID: 25529582).

The etiology of epilepsy is heterogeneous and includes monogenic causes, purely environmental origins, and complex forms involving multiple genes, modifier genes and/or environmental factors (Lemke et al. 2012. PubMed ID: 22612257; Wilmshurst et al. 2015. PubMed ID: 26122601). Mild forms of epilepsy may be inherited as a familial trait; however, many epilepsy cases are sporadic, occurring in families with no prior history of seizure (Allen et al. 2013. PubMed ID: 23934111). Sporadic epilepsy may be inherited by X-linked or autosomal recessive transmission, but is more commonly caused by dominant, de novo variants in neuronally-expressed genes. De novo pathogenic missense variants are especially common among genetic epilepsies. For example, missense variants in ion channels (channelopathies) may modify gating kinetics, ion permeability, voltage sensitivity or ligand-binding imparting both gain- or loss-of-function effects (Kullmann. 2002. PubMed ID: 12023309). In addition a large number of epilepsy-related genes are sensitive to null mutation, and chain-terminating variants are well-documented to be pathogenic (Human Gene Mutation Database). Finally, rare cases of epilepsy have been attributed to copy number changes involving epilepsy-related genes.

This test includes genes that through literature, OMIM, and HGMD searches have at least a potential association with ASD, ID and epilepsy phenotypes. The full list of genes sequenced in this test is available under the “Summary and Pricing” tab.

Testing Strategy

The Intellectual Disability, Epilepsy, and Autism (IDEA) Panel offers traditional Patient Only testing as well as the options of Family testing (e.g., Duo, Trio, etc.) or Patient Plus testing. For Patient Plus, we require specimens from both biological parents along with the patient’s specimen. However, panel testing is performed only on the patient’s specimen, and depending on variants identified, parental specimens are then used for targeted testing to determine the phase of variants or to determine if a variant occurs de novo. For the highest diagnostic rate, Family - Trio testing is recommended.

For the Intellectual Disability, Epilepsy, and Autism (IDEA) Panel, we use Next Generation Sequencing (NGS) technologies to cover the coding regions of targeted genes plus ~10 bases of non-coding DNA flanking each exon. As required, genomic DNA is extracted from patient specimens. Patient DNA corresponding to these regions is captured using Agilent Clinical Research Exome hybridization probes. Captured DNA is sequenced on the NovaSeq 6000 using 2x150 bp paired-end reads (Illumina, San Diego, CA, USA). The following quality control metrics are generally achieved: >97% of target bases are covered at >20x and mean coverage of target bases >120x. Data analysis and interpretation is performed by the internally developed Infinity pipeline. Variant calls are made by the GATK Haplotype caller and annotated using in house software and Jannovar. Common benign, likely benign, and low quality variants are filtered from analysis.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All reported CNVs are confirmed using another technology such as aCGH, MLPA, or PCR.

The report will not include all the observed rare variants due to the large number of genes included in the Intellectual Disability, Epilepsy, and Autism (IDEA) Panel. However, the list of rare variants is available along with our interpretations upon request. Since this test is performed using exome capture probes, a reflex to exome sequencing may be ordered. Please see the PGxome page (Test #5000) for limitations and reporting criteria for this test.

Clinical Sensitivity

The Intellectual Disability, Epilepsy, and Autism (IDEA) Panel diagnostic yield for trio tests correspond closely to the diagnostic rate of ASD-ID exome testing found in the literature (~28%), since this panel includes hundreds of genes implicated in these phenotypes. 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 & 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). Similar genetic heterogeneity is observed in patients with intellectual disability, and diagnostic yields of up to ~40% have been reported in trio whole exome sequencing studies (Vissers et al. 2016, PubMed ID: 26503795; Bass and Skuse. 2018. PubMed ID: 30138136).

The Intellectual Disability, Epilepsy, and Autism (IDEA) Panel is also predicted to identify pathogenic variants in 37% of early infantile epileptic encephalopathy cases with unknown cause (Della Mina et al. 2015. PubMed ID:24848745; Wang et al. 2014. PubMed ID:24818677; Ream et al. 2014.PubMed ID:25108116). In particular, clinical sensitivity for autosomal dominant nocturnal frontal lobe epilepsy is more than 25-35%, while for autosomal dominant focal epilepsy, the sensitivity is more than 12-37% (Dibbens et al. 2013. PubMed ID:23542697; Picard et al. 2014. PubMed ID:24814846). This panel could identify pathogenic variants in more than 90% of Dravet syndrome patients (Carvill et al. 2014. PubMed ID:24623842).

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, we recommend trio-based testing in order to maximize the clinical sensitivity of this test.

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 the Intellectual Disability, Epilepsy, and Autism (IDEA) Panel and can be ordered using Test Code #558.

Reporting: Reports will consist of two different sections:

  • Variants in genes known to be associated with the provided phenotype
  • Variants in genes possibly associated with the provided phenotype

All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories (Pathogenic, Likely Pathogenic, Variant of Uncertain Significance, Likely Benign and Benign) per ACMG Guidelines (Richards et al. 2015. PubMed ID: 25741868). Pathogenic, Likely Pathogenic and Variants of Uncertain Significance considered to contribute to the proband's phenotype will be reported in the first and second sections. While this panel is exome-based, we will NOT be reporting secondary findings or carrier status variants unrelated to the patient’s clinical features.

Human Genome Variation Society (HGVS) recommendations are used to denote sequence variants (http://www.hgvs.org).

Limitations and Other Test Notes: Interpretation of the test results is limited by the information that is currently available. Enhanced interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder accumulate. A negative finding does not rule out a genetic diagnosis.

When sequencing does not reveal any heterozygous differences from the reference sequence, we cannot be certain that we were able to detect both patient alleles. Occasionally, a patient may carry an allele which does not capture or amplify, due to a large deletion or insertion. In these cases, the report will contain no information about the second allele.

For technical reasons, the Intellectual Disability, Epilepsy, and Autism (IDEA) test is not 100% sensitive. Some exons cannot be efficiently captured, and some genes cannot be accurately sequenced because of the presence of multiple copies in the genome. Therefore, a small fraction of sequence variants relevant to the patient's health will not be detected.

In general, sensitivity for single, double, or triple exon CNVs is ~70% and for CNVs of four exon size or larger is >95%, but may vary from gene-to-gene based on exon size, depth of coverage, and characteristics of the region. 

We sequence coding exons for most given transcripts, plus ~10 bp of flanking non-coding DNA for each exon. Unless specifically indicated, test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions, uncharacterized alternative exons, chromosomal rearrangements, repeat expansions, epigenetic effects, and mitochondrial genome variants.

In most cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative variants for recessive disorders, we cannot be certain that the variants are on different alleles, unless parental specimens are also tested.

Our ability to detect minor sequence variants due to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient's nucleated cells may not be detected.

This test targets most, but not all, of the coding parts of genes within the panel (called exons).

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during amplification.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes if taken from whole blood). Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics. However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

Genetic counseling to help to explain test results to the patients and to discuss reproductive options is recommended.

Indications for Test

This test is primarily indicated for patients with ID, epilepsy, and/or ASD who are negative for Fragile-X syndrome (particularly males). The FMR1 CGG-repeat expansion (Test #558) test is available to individuals who have not been previously tested.

Related Tests

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Top 99 Genetic Causes of Developmental Delay Panel
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Citations

  • Allen et al. 2013. PubMed ID: 23934111
  • American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 2000. Text Revision. 4.
  • Bass and Skuse. 2018. PubMed ID: 30138136
  • Bourgeron. 2015. PubMed ID: 26289574
  • Bowling et al. 2017. PubMed ID: 28554332
  • Carvill et al. 2014. PubMed ID: 24623842
  • Christensen et al. 2016. PubMed ID: 27031587
  • Della Mina et al. 2015. PubMed ID: 24848745
  • Dibbens et al. 2013. PubMed ID: 23542697
  • Fisher et al. 2017. PubMed ID: 28276064
  • Fitzgerald. 2015. PubMed ID: 25533962
  • Human Gene Mutation Database (Biobase).
  • Ilyas et al. 2020. PubMed ID: 31984132
  • Iossifov et al. 2014. PubMed ID: 25363768
  • Jensen and Girirajan. 2017. PubMed ID: 29241461
  • Karam et al. 2015. PubMed ID: 25728503
  • Kaufman et al. 2010. PubMed ID: 21124998
  • Kullmann. 2002. PubMed ID: 12023309
  • Larsen et al. 2016. PubMed ID: 27790361
  • Lee et al. 2014. PubMed ID: 25326637
  • Lemke et al. 2012. PubMed ID: 22612257
  • Levy et al. 2009. PubMed ID: 19819542
  • Li et al. 2016. PubMed ID: 25849321
  • Lichtenstein et al. 2010. PubMed ID: 20686188
  • Maenner et al. 2020. PubMed ID: 32214087
  • McPartland et al. 2016. Encyclopedia of Mental Health. 2: 124-130. PubMed ID: absent
  • Milani et al. 2015. PubMed ID: 27617122
  • Miller et al. 2010. PubMed ID: 20466091
  • Ngugi et al. 2011. PubMed ID: 21893672
  • Picard et al. 2014. PubMed ID: 24814846
  • Ream et al. 2014. PubMed ID: 25108116
  • Retterer et al. 2016. PubMed ID: 26633542
  • Richards et al. 2015. PubMed ID: 25741868
  • Rylaarsdam and Guemez-Gamboa. 2019. PubMed ID: 31481879
  • Sabo et al. 2020. PubMed ID: 32767738
  • Schaefer and Mendelsohn. 2008. PubMed ID: 18197051
  • Schaefer and Mendelsohn. 2013. PubMed ID: 23519317
  • Scheffer et al. 2017. PubMed ID: 28276062
  • Sztainberg and Zoghbi. 2016. PubMed ID: 27786181
  • Vasudevan and Suri 2017. PubMed ID: 29196358
  • Vissers et al. 2016. PubMed ID: 26503795
  • Vorstman et al. 2017. PubMed ID: 28260791
  • Wang et al. 2014. PubMed ID: 24818677
  • Wang et al. 2020. PubMed ID: 32429945
  • Wilmshurst et al. 2015. PubMed ID: 26122601
  • Woodbury-Smith and Scherer. 2018. PubMed ID: 29574884
  • Wright et al. 2015. PubMed ID: 25529582
  • Yuen et al. 2015. PubMed ID: 25621899

Ordering/Specimens

Ordering Options

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details