When a child presents with developmental delay or an intellectual disability, the physician faces a bewildering diagnostic challenge. There are thousands of possible causes, with overlapping signs and symptoms that in many cases prevent a definitive diagnosis based on clinical grounds alone.
To help physicians meet that challenge, Athena Diagnostics® and Personalis®, Inc. have developed the NeuromeTM, a neurologically-focused exome test, designed to reveal causative mutations across the neuro-exome.
“About 85% of whole-exome sequencing is ordered for neurological conditions such as developmental delay” explains Joseph Higgins, MD, the Laboratory Director at Athena Diagnostics and the Medical Director for Neurology at Quest Diagnostics. “But the problem with performing a whole exome is that you get a lot of incidental and non-specific findings. That confuses the clinical picture.” By focusing sequencing efforts on genes that specifically impact the nervous system, the confidence in a positive result is increased.
Just as important, the focus on neurologically related genes means depth of coverage can be increased, improving the chances for a diagnosis. When a mutation occurs in a region of the gene not deeply sequenced by standard whole-exome analysis, the mutation may be missed, or the confidence in the result may be reduced. The deeper coverage in the most relevant genes leads to higher yield and greater diagnostic confidence.
Typical candidates for Neurome analysis are children with some aspect of delayed neurodevelopment, including walking or talking, or evidence of neurodevelopmental disability, such as autism of 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 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 more targeted testing first,” Dr. Higgins says, both to limit cost and to reduce the likelihood of incidental findings that don’t improve the understanding of the condition.
Neurome testing is also available for parents. Trio analysis—sequencing the child and both parents—is an important option when Neurome results in the child reveal multiple variants of unknown, but potentially pathogenic, significance. “If both parents are negative for a specific variant, that increases the likelihood that a de novo variant is responsible for the disorder in the child,” Dr. Higgins says. On the other hand, he said, if analysis in the child reveals a mutation that is highly likely to be causative, there may be no need to test the parents. “We may recommend testing in some cases when the significance of a genetic variant is unclear.” In every case, Dr. Higgins stresses, “there is no substitute for doing a thorough neurological exam.” The exam not only confirms the neurological nature of the condition, but helps locate the lesion in the neuraxis. In many cases, that can help focus testing, and assist in the interpretation of results, even further. “When high-quality clinical information is combined with appropriate genetic testing, you are more likely to get your neurological answer.”