Neurome - Exome Sequencing for Neurological Disorders

Higgins, Joseph J., MD., FAAN
Laboratory Director, Athena Diagnostics
Medical Director, Neurology, Quest Diagnostics
Marlborough, MA
Also by this Author 

Advances enabled by the human genome project have led to testing capabilities which generate vast amounts of genetic data. Identifying clinical useful information from within the mass of data has become a significant challenge.  

Dr. Joseph J. Higgins, Laboratory Director, Athena Diagnostics and Medical Director, Neurology, Quest Diagnostics, discusses the challenges of identifying clinically relevant information from whole exome sequencing and explains how analysis provided by Neurome™, a service based on whole exome sequencing, provides clinicians with relevant information to support the diagnosis of neurological disorders.

The Impact of the Human Genome Project

As a participant in the human genome project, Dr. Higgins has seen first-hand the considerable diagnostic advances achieved since the project was launched in the late 1980s. “What’s amazing to me is that with today’s diagnostic technology – next generation sequencing - we can now perform in a day something which took us over ten years to achieve,” he says. “Over the course of the project, we moved from an era where you had to physically map regions that were linked to different disease states to one where you could design your own PCR parameters and Sanger sequencing based on information available on the web. Today, in the digital age, massively parallel sequencing capabilities, combined with good databases, have made genetic testing widely available and provided the basis for personalized genomic medicine.”

The Role of Exome Sequencing

The wider availability of genetic testing has raised questions about the appropriate use and usefulness of certain tests, in particular whole genome sequencing.1 One application, which has been shown to have clear clinical utility is the use of exome sequencing in pediatric neurology. Whole exome sequencing focuses on the exome, the 1-2% of the human genome that codes for proteins and where most known disease-causing genetic variants occur.1 As a result, exome testing  targets the most clinically actionable genomic regions for the individual patient as compared to whole genome sequencing. In pediatric neurology, it is most commonly used to identify causes of developmental delay and this use accounts for about 85% of exome testing.

The traditional approach to identify a developmental disorder includes performing a chromosome microarray to look for deletions and duplications based on the physician’s clinical assessment. If that is negative, it would be followed by targeted testing if a syndrome is recognized or whole exome sequencing. In addition to these cases where targeted testing does not identify a cause, exome testing may also be appropriate in the following cases: a patient’s medical history and physical examination suggest a neurological disorder of unknown cause with suspected genetic etiology; a patient presents with a highly heterogeneous disorder; a patient presents with a likely genetic disorder but targeted testing is not available.1

Targeted Testing for Neurology – Neurome™

“The challenge with performing a whole exome,” says Dr. Higgins, “is that you get a lot of incidental and non-specific findings, which confuses the clinical picture. For instance, if someone has an enlargement of the liver and spleen, in looking for a causative genetic disorder you should only look at those genes linked to enlargement of the liver or the spleen. But, if you look at the whole exome, you could also get information about the brain and heart. With the test that we now have available, called Neurome™, we only provide information that is specific to the brain, spinal cord, peripheral nerve, neuromuscular junction and muscle; in other words the nervous system. By focusing sequencing efforts on genes that specifically impact the nervous system, the confidence in a positive result is increased. More importantly we integrate  information from whole exome sequencing with computational phenotypic algorithms to extract the relevant data that applies to the neurologic condition. This information, when combined with a physician’s clinical findings, becomes very powerful and facilitates a definitive diagnosis.”

Selecting Data Relevant to Clinical Findings

Neurome™ is designed to take into account a physician’s clinical findings, notes Dr. Higgins. “We only select the disease genes that are relevant to the particular constellation of signs and symptoms a clinician has observed. If we selected all the variants, or potentially pathogenic variants, there would be a very long list, and the physician would have difficulty identifying, which was relevant. Instead, we provide the physician with a test report with sequencing findings and a clinical interpretation specific to the patient's suspected disorder.”

Dr. Higgins goes to on to explain how Neurome™ provides this clinically relevant information. “It’s a matter of combining the phenotype - clinical signs and symptoms – with the massive amount of genetic information that is now available. In order to filter that information, we need to have the clinical information upfront so that we can query clinical databases and rank order signs and symptoms based on their pertinence to neurologic disease,.  We thenrank order the pathogenicity of the particular DNA variants that an individual patient of their family member possesses..”

“We supplement the clinical or phenotype component, with relevant sequencing data,” continues Dr. Higgins. “We look at all the genes that have been expressed in the nervous system, and make sure there is adequate co-coverage in those genes. With whole exome testing there can be peaks and valleys in the amount of coverage for certain areas in the gene, meaning that you can't reliably make a base pair call. We boost those problematic areas so we get adequate coverage of those genes.   The phenotype information helps filter the variants that are associated with the specific clinical picture. When a mutation occurs in a region of a gene not deeply sequenced by standard whole-exome analysis, the mutation may be missed, thus, the confidence in the result may be reduced. Deeper coverage in the most relevant neurologic genes leads to a higher yield and greater diagnostic confidence.”

“So, Neurome™ differs from other exome testing due to the way it filters information based on phenotype and enhances coverage by boosting or finishing certain genetic regions relevant to neurology,” summarizes Dr. Higgins.

Application of Neurome™ Analysis

Typical candidates for Neurome™ analysis are children with some aspect of delayed milestones, including walking or talking, or evidence of a neurodevelopmental disability, such as autism or multiple congenital anomalies. Adults may also be candidates for Neurome™ analysis, when targeted testing is not informative. Disorders whose genetic basis may be revealed also include neuromuscular disorders, motor neuron diseases, hereditary peripheral neuropathies, movement disorders (e.g. Parkinson disease), hearing loss, epilepsy, leukodystrophy, and early-onset dementia. Importantly, the clinical picture should be one which does not correspond to a specific disorder, or for which a specific gene test or targeted panel doesn’t exist. “Current recommendations from the American College of Medical Genetics are to do the targeted genetic testing first,” Dr. Higgins says, both to limit cost and to reduce the likelihood of incidental findings that don’t improve the diagnostic understanding of the condition being tested.2




  1. Rehm HL, Bale SJ, Bayrak-Toydemir P, et al.  ACMG clinical laboratory standards for next-generation sequencing. Genet Med. 2013Sep;15(9):733-47. doi: 10.1038/gim.2013.92.
  2. Green RC, Berg JS, Grody WW et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing Genet Med. 2013Jul;15(7):565-74. doi: 10.1038/gim.2013.73.