Genetic Testing


Genetic testing is an ever-expanding avenue for characterization of many neurological syndromes, including infantile spasms. Although the bulk of genetic testing in the context of infantile spasms has historically been conducted for research purposes, there are new opportunities for clinically-relevant testing. Specifically, the results of genetic testing may (1) identify the cause of infantile spasms, (2) impact the choice of medication or other therapy, and (3) guide decisions for family-planning. However, genetic testing is not indicated for all patients with infantile spasms—especially those with specific causes already identified, or suspected causes which are not genetic in origin (e.g. acquired head injury).

There is no single genetic test, or set of tests, that applies to all patients. The test or testing strategies conducted should be tailored to individual patients and families. Furthermore, the selection of tests should be guided by discussion with the treating neurologist as well as a geneticist and genetic counselor. The results of genetic testing can have a tremendous impact on the patient as well as other family members.

There is a rapidly growing list of genes that have been linked to infantile spasms. However, not all patients with mutations (abnormal DNA sequences) of these genes develop infantile spasms. It is unknown why some patients with mutations in these genes develop infantile spasms and others do not, and this is an area of intense ongoing research. In addition, there are numerous observed patterns of extra DNA (duplications, expansions, or trisomy) or missing DNA (deletions) which are associated with infantile spasms, even though the genes responsible for infantile spasms in these regions of extra or missing DNA have yet to be identified or fully characterized. Beyond abnormal gene sequences, gene-expression (the production of proteins based on DNA "blueprints") also plays an important role in the development of infantile spasms.

Single-Gene Testing

In general, if a specific gene-mutation is suspected based on characteristic findings in a given child, we simply search for that particular mutation by sequencing a single gene (or a few genes). For example, this is typical in the effort to confirm Tuberous Sclerosis Complex, in which the TSC1 and TSC2 genes are sequenced.

Chromosomal Microarray

More often, a genetic cause of infantile spasms is suspected based on the lack of other identified causes (e.g. brain injury, brain malformation), but no particular gene is specifically targeted. In this case, it is typical to first search for extra pieces of DNA (e.g. duplication of genetic material) or missing pieces of DNA (i.e. deletions of genetic material) using a test called a chromosomal microarray (also called array comparative genomic hybridization or “aCGH”). This test has a yield of approximately 5 to 10%, meaning that among all children with infantile spasms whose cause is unknown, a chromosomal microarray will uncover deletion of duplication that likely caused infantile spasms in 5 to 10% of cases. In some cases, a suspicious deletion/duplication may prompt testing of parents (who presumably did not have infantile spasms) to better determine whether the suspicious duplication/deletion is truly the culprit.

Epilepsy Gene Panel

If a chromosomal microarray does not detect deletion/duplication, a typical next step is an epilepsy gene panel. This is a test in which approximately 50 to several hundred genes (this varies by the laboratory that conducts the testing) linked to epilepsy and infantile spasms are sequenced, with the intent to search for small duplications/deletions (e.g. within a single gene) that are missed by chromosomal microarray analysis, or more commonly, to search for single nucleotide (a single “letter” of DNA code) that changes the sequence and function of the protein “coded” by a given gene. The yield of epilepsy gene panels is about 20%. As in the case of chromosomal microarray, a suspicious sequence variation may prompt parental testing.

Clinical Exome Sequencing

If both a chromosomal microarray and an epilepsy gene panel do not identify a suspected genetic cause of epilepsy, a typical next step is a test called clinical exome sequencing (also called whole exome sequencing). This is usually conducted as a “trio” meaning that samples (usually blood) are obtained from a patient and both parents (again presumably without history of infantile spasms). With this test, all 22,000 human genes in the patient and both parents are sequenced, and the sequences of the patient and parents are systematically compared to search for gene changes—especially new (“de novo”) mutations that are present in a patient’s DNA sequence but not observed in the parents’ DNA sequences. This testing has a yield of approximately 40%.

Whole Genome Sequencing

Whole genome sequencing has been touted as the next great genetic testing strategy for human disease. However, although the technology is now available to sequence the entire genome (not just the exome), our ability to make sense of sequencing data is still very limited. At present, the yield of whole genome sequencing is not meaningfully superior to clinical exome sequencing. 

Benefits of Genetic Testing

The main benefit of genetic testing is that it may identify the cause of infantile spasms. This can (1) relieve some of the anxiety that is caused by simply not knowing why a child has infantile spasms, (2) steer a patient toward a specific therapy that is known to be especially effective for a given patient, and (3) guide parental decision-making regarding future children.

Risks of Genetic Testing

  1. Cost: Genetic testing can be quite expensive, and insurance reimbursement varies greatly depending on the specific test, the insurance provider, and characteristics of individual patients (i.e. factors that affect the likelihood that a genetic cause can be found). Without insurance coverage, single-gene testing generally costs approximately $1000 (USD) per gene, chromosomal microarray costs approximately several hundred dollars (USD), epilepsy gene panels costs several thousand dollars (USD), and clinical exome sequencing costs several thousand (but generally <$10,000 USD). There are of course cases in which this testing is warranted and makes sense medically and financially, and such costs are appropriately covered by insurance. However, given these costs, considerable documentation/negotiation is required of physicians and parents to demonstrate that such testing is indeed warranted.
  2. Stress: Considerable psychological stress may accompany the discovery of genetic abnormalities that cause infantile spasms. Although irrational, parents often feel guilt upon discovering that one or both parents have passed on a genetic change that contributes to the development of infantile spasm, even though no one is at fault.
  3. These new genetic testing methods introduce the possibility of encountering unexpected results—which can be extremely stressful. For example, genetic testing might reveal that a patient’s father is not actually the biological father, or testing might reveal that a parent is at risk to develop of epilepsy later in life, or at risk to develop another disease that could have significant impact on quality of life, life-expectancy, etc. Many people initially believe they would want to be aware of such findings, but after discovery of these sorts of unexpected results, many patients/parents have remorse, especially in those cases in which nothing can be done, or the results are inconclusive. For instance, imagine discovering that you have a 50% chance of developing an untreatable, devastating disease. Although many people would want to know this information, many would not. This is an important consideration before undertaking any genetic testing, especially if it involves parental testing or may prompt parental testing.



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