HUNTSVILLE, Alabama (GenomeWeb) – Clinical sequencing can sometimes provide patients with suspected genetic disease with a sought-after molecular diagnosis, or even a treatment, but often, the test results do not change their treatment or care.
Several speakers at the 2018 Genomic Medicine Conference held here by the HudsonAlpha Institute for Biotechnology recounted cases that showcased the impact sequencing-based testing has had on their clinical practice.
In some rare instances, clinical sequencing can not only uncover the genetic cause of a patient's condition, but also point to a treatment path. Vandana Shashi, a pediatrician and clinical geneticist at Duke University School of Medicine, for example, described the case of a 20-month-old girl with an unsteady gait, weakened extremities, and nystagmus, among other symptoms. The girl's cognition was normal, and the disease appeared to be progressive.
Trio genome sequencing of the girl and her parents found that the girl had compound heterozygous mutations in the SLC52A2 gene, which encodes a riboflavin transporter, suggesting she had a riboflavin transporter deficiency. She has since been treated with high doses of riboflavin — Shashi noted the patients' parents gave her the first dose before even leaving the building — and her symptoms have receded.
An outcome like this, Shashi said, is "a dream for us in genetics."
But it's not always the case, and sometimes, genetic testing provides not even a clear-cut diagnosis. Meagan Cochran, for example, a genetic counselor at HudsonAlpha, talked about the story of a 74-year-old man with neuropathy who'd started exhibiting symptoms such as a dragging foot or tingling extremities when he was 71 years old. After an EMG, he was diagnosed with mild length-dependent sensory axonal neuropathy. His mother and brother had also experienced tingling and numbness, which Cochran noted weren't strong symptoms, but suggested that it might be a genetic condition.
For this man, whole-genome sequencing uncovered a variant of uncertain significance in the gene SPTLC2, which is associated with hereditary sensory autonomic neuropathy C, giving him a potential but not a definite diagnosis. Cochran said his symptom overlap with this condition was decent, though he was older than the usual age of onset. She added that his brother was also tested and had the same variant.
A recent study suggested that L-serine supplementation might be a possible treatment for patients diagnosed with the disease, Cochran said, but the genetic result alone does not support such treatment. However, sphingolipid levels are also linked to this condition, and the man is currently awaiting his sphingolipid test results to see if he can be diagnosed that way.
"In a lot of cases, quite a bit of uncertainty can be left" following genetic testing, she said.
Other times, clinical sequencing changes a patient's diagnosis but not their treatment or care. Cochran also presented a case study of a 54-year-old man thought to have primary lateral sclerosis. He'd first experienced symptoms at the age of 38, such as progressive lower limb spasticity and slurred speech, and was diagnosed with PLS at age 44.
He later sought more information about the condition, Cochran said, because he wanted to know whether his son might be affected. Whole-genome sequencing found two recessive pathogenic variants in the SPG7 gene, which are associated with spastic paraplegia 7 rather than PLS. His son, she noted, is unlikely to be affected by the disease because he is heterozygous for the mutation, but he is a carrier.
In this case, she said, genetic testing changed the man's diagnosis, noting that clinically, PLS and SP7 are indistinguishable.
Another example of Cochran's where DNA testing changed the diagnosis but not the treatment was that of a 66-year-old woman with symptoms of dementia that started at age 63. The patient, whose mother also had dementia, was initially diagnosed with frontotemporal dementia.
After whole-genome sequencing, that diagnosis changed to adult-onset leukoencephalopathy with axonal spheroids and glia, due to a likely pathogenic variant in CSF1R. Her MRI was consistent with the condition as well, according to Cochran.
But the change in diagnosis didn't lead to a change in prognosis, she noted, as both conditions lead to progressive decline.
Other times, nothing at all is found through genetic testing. Chris Gunter from the Marcus Autism Center and Emory School of Medicine said her center recommends genetic testing for its patients with autism spectrum disorder, though it doesn't require it.
Over the course of 12 months, she said, they analyzed 230 cases of children with autism to find 13 copy-number changes, one FMR1 variant, one TSC variant, one NF1 variant, and no PTEN variants. In one particular case of a six-year-old boy, they uncovered a copy number loss affecting a VUS, the clinical significance of which she said was unclear. Results like that, she said, are "what we see the most of in autism."
"We spent the vast majority of our time giving negative results," Gunter added, noting that the families say they still value genetic testing.