PGmax^TM - Intellectual Disability, Epilepsy, and Autism (IDEA) Panel

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 44 individuals with a male-to-female ratio of 4:1 (Maenner et al. 2021. PubMed ID: 34855725). While ASD can be diagnosed as early as 18 months, meta-analyses report patients are diagnosed on average by age 5 and that numerous factors impact the age of diagnosis (van 't Hof et al. 2021. PubMed ID: 33213190; Hyman et al. 2020. PubMed ID: 31843864). 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). Earlier diagnosis has been reported to correlate with improved cognitive and language abilities (Clark and Barbaro. 2018. PubMed ID: 28905160; van 't Hof et al. 2021. PubMed ID: 33213190).

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).

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.

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 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 >100x. 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.

For the repeat expansion screen, available on the PGnome platform, individuals with phenotypes consistent with FMR1-related disease will be evaluated for expansions in this gene. Our genome test screens for expanded allele repeat sizes in FMR1 with nearly 100% analytical specificity and sensitivity. Any potential expansions detected by the screening test will be confirmed with the appropriate confirmatory clinical repeat expansion test. Only those expansions that are confirmed will be reported.

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. 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). Please see the PGxome page (Test #5000) for limitations and reporting criteria for this test.