A major challenge in modern genetic testing is determining whether a new variant is benign or pathogenic. For Michael Waters, MD, PhD, of the McKnight Brain Institute at the University of Florida in Gainesville, that challenge led him to a new discovery about a gene for spinocerebellar ataxia. And that discovery allowed him to help one family help their son, born with a rare form of the disease.
Spinocerebellar ataxia (SCA) can be caused by a large number of genes. In 2006, Dr. Waters led a team that discovered that SCA13, a locus on chromosome 19, encoded a voltage-gated potassium channel (KCNC3) with enriched expression in the cerebellum. The Filipino family in which the gene was identified carried a mutation that converted amino acid 420 from an arginine to a histidine (R420H). Subsequent investigations in both American and European populations identified further cases of R420H, but also other variants, whose significance was unknown.
In order to make progress in understanding the clinical consequences of new SCA13 variants, Dr. Waters partnered with Athena Diagnostics. For over two years, when Athena reports a finding of unknown significance for a SCA13 test, a letter from Dr. Waters is included to the physician, offering to assess the pathogenicity of the variant in the laboratory, by testing the biophysical properties of the potassium channel encoded by the variant allele. There is no cost to the patient or physician, and all information is kept strictly confidential.
One variant Dr. Waters has identified as pathogenic through this process is R423H, first identified in a family in the northeastern United States affected through at least three generations with motor and cognitive deficits. “That was the first time that we had pretty conclusive evidence that R423H was causative,” Dr. Waters says. “Because we had the familial genetics and because the disease segregated with that allele through a multigenerational family, and because we had the complementary laboratory results, which demonstrated the altered biophysics,” it was clear the variant was causing the disease. “That was pretty exciting, to be able to add that as a causative allele.”
But even more exciting, he says, is what happened next. Shortly after that discovery, the same variant was found in a test of an infant boy from the northwest, who presented at 7 months with seizure-like episodes. After his letter went out with the results, Dr. Waters was contacted by the family. His work on R423H was so new that, even though they had the test result, “They had no idea what to expect,” he says. Not only could Dr. Waters tell them that in all likelihood, their son’s symptoms were due to the gene mutation, but he could also give them some encouraging news.
One of the challenges with SCA13 is that each pathogenic variant is associated with a different phenotype, and a different natural history, so prognosis is difficult without evidence from other individuals with the same mutation. But in the case of R423H, Dr. Waters had it. In the family from the northeast, the disease was not progressive. “In fact, they got better over the first two decades of life,” he says. As a child, one of the boys of the family required a wheelchair for mobility, but by high school was using only a cane, and in adulthood, he walks unassisted. He retains some cognitive impairment, but he graduated from high school and now is gainfully employed.
Based on the genetic test results, Dr. Waters says, “I was able to tell the family from the northwest, ‘First your search is over. In all likelihood, this is what is causing your son’s problems.’ Second, I was able to reassure them that in another family with the same mutation, the disease didn’t progress and the child improved. That’s a nice thing to be able to say to a couple of very concerned parents.” That knowledge gave the parents information that helped them advocate for ongoing intensive physical, occupational, and speech therapy for their child.