Feb. 22, 2017
Genetic involvement in the pathogenesis of neurological disease is significant. Among the approximately 6,400 phenotypic entries in cataloged inherited human diseases, central nervous system disorders account for approximately 60 percent, and peripheral nervous system disorders for approximately 15 percent.
For the past decade, next-generation sequencing (NGS) has been used to identify genetic causes for neurological conditions. In patients with nonspecific neurological disorders — such as children with developmental delay, where an extensive number of genetic differentials exist — whole-genome sequencing (WGS) and whole-exome sequencing (WES) have shown promise in identifying genetic causes. For patients diagnosed with a focused disease category such as inherited neuropathy, myopathy, neuromuscular junction disease, or motor neuron or epilepsy syndromes, targeted NGS panels can be efficacious and cost-effective. However, choosing appropriate genes for targeted NGS panels requires strong clinical expertise as well as genetic knowledge.
To facilitate diagnosis of genetic neurological diseases, Mayo Clinic in Rochester, Minnesota, has launched a neurology genomics clinic. In collaboration with Mayo Clinic's Center for Individualized Medicine, the neurology genomics clinic brings together clinicians, laboratory geneticists, bioinformaticians and genetic counselors to enhance treatment and research of genetic neurological conditions.
"At Mayo Clinic, we talk about matching the right patient with the right doctor. Similarly, we want to match the right patient with the right test," says Christopher J. Klein, M.D., a consultant in Neurology at Mayo Clinic in Rochester, Minnesota.
"When patients come to us with genetic conditions, including complex neurological conditions, we establish a detailed phenotype," says Ralitza H. Gavrilova, M.D., a consultant in Neurology and Clinical Genomics at Mayo Clinic's campus in Minnesota. "After genetic testing we deliver a diagnosis, recommend treatment, and offer screening and genetic counseling for family members as needed."
Collaboration between clinic and lab
Establishment of a specific genetic diagnosis
B. Two heterozygous variants were identified in the FA2H gene, consistent with a diagnosis of autosomal recessive spastic paraplegia type 35.
Disease-targeted whole-exome next-generation sequencing (NGS)
Whole-exome next-generation sequencing (NGS) is best for diagnostic odyssey cases where neurological localization is not well-established or genetic differential is not limited to any specific disease category. Disease-targeted NGS provides the best performance metrics for conditions with a defined genetic differential. Single-gene testing remains effective for neurological phenotypes with very specific characteristics. Image reprinted with permission from Mayo Clinic Proceedings.
Moderate to severe diffuse parenchymal volume loss
A. MRIs demonstrate moderate to severe diffuse parenchymal volume loss, somewhat disproportionately affecting the brainstem and cerebellum. There is considerable apparent white matter loss of the cerebral hemispheres, and faint ill-defined periventricular white matter signal abnormality.
Establishing a specific genetic diagnosis can avoid the use of improper therapies as well as additional costly and invasive testing such as biopsy. In the neurology genomics clinic, patients have complete neurological examinations, including electromyography, electroencephalography, MRI, nerve-conduction tests, and tests of muscle, nerve and brain pathology, as appropriate. Neurologists and laboratory geneticists discuss the results and arrive at a recommendation for testing each individual patient.
"The phenotypic presentations for patients with neurogenetic disorders are diverse and often overlapping. We work closely with our clinical colleagues to make sure that, based on the patient's phenotype, the right type of testing has been ordered," says Kevin C. Halling, M.D., Ph.D., a consultant in Laboratory Genetics at Mayo Clinic's campus in Minnesota. "We also work closely with our clinicians in the interpretation of the NGS results."
WGS analyzes an entire genome, composed of approximately 3 billion base pairs of DNA sequence. WES covers all protein-coding regions of the human genome, totaling about 50 million base pairs or 1.5 percent of the genome. Both procedures can produce a large number of genetic variants of unknown significance and, despite the nomenclature, have incomplete coverage of genes and exons. Targeted NGS panels start with the capture of a set of disease-focused genes followed by massive parallel sequencing. A targeted panel might only cover up to several million base pairs, and approximately 50 to 300 genes.
Nevertheless, a well-targeted panel can yield a diagnostic rate similar to WES. Mayo Clinic is developing NGS panels for peripheral neuropathy, epilepsy and neuromuscular disorders. The inherited neuropathy algorithm uses multiple criteria, including age of symptom onset, specific sensory features, ataxic or pyramidal features, and nerve conduction studies. "If a certain phenotype has a couple of hundred genes with high potential for causing disease, it makes sense to focus on them with a targeted panel," Dr. Klein says.
When multiple genetic factors appear to be involved, WES might be recommended. If NGS finds rare functional variants in novel genes, the case is further investigated.
"When we suspect a new genetic mutation, we can collect samples from family members. Then, using WGS and functional studies, we can try to confirm that those genes are causing the problem," Dr. Gavrilova says. "We can make a diagnosis, recommend screening for family members, including prenatal screening, and work with genetic counselors to educate patients."
For patients, the neurology genomics clinic provides testing, diagnosis, treatment, counseling and research beneath a single roof. "Patients are happy most of all to have a diagnosis," Dr. Gavrilova says. "They also are generally excited to participate in research. We form a very strong bond with the families we treat.
"With the resources of the neurology genomics clinic, we are connecting with researchers and different centers," she adds. "We are creating a network that ultimately will benefit patients with these diseases."