eP088: Diagnosing a patient with progressive myoclonic epilepsy-12 with variants of uncertain significance on exome sequencing

Progressive myoclonic epilepsy-12 (EPM12) is a rare autosomal recessive neurologic condition characterized by tonic-clonic seizures, myoclonus, and cerebellar ataxia associated with progressive cerebral and cerebellar atrophy on brain imaging. EPM12 is associated with variants in the SLC7A6OS gene. It is a progressive condition in which most lost ambulation and become wheelchair bound as adults. We present a young adult identified with variants in the SLC7A6OS gene through exome sequencing (ES). The patient is a 22-year-old female that has been followed by the genetics clinic since she was 13 years of age. She was born following an uncomplicated pregnancy to consanguineous parents of Asian Indian ethnicity who are first cousins. Developmentally, she had delays in fine and gross motor skills. Myoclonus developed at age 12 and she was diagnosed with dysarthria, cerebellar ataxia, a movement disorder, and borderline intellectual disability at age 13. An MRI was normal, EEG revealed paroxysmal spike and wave discharges, and vEEG was suggestive of myoclonic seizures and diffuse cerebral dysfunction. She was diagnosed with juvenile myoclonic epilepsy. She later developed dystonia/ataxia and vocal cord dysarthria as an adult, as well as breakthrough seizures. Microarray was initially performed which revealed no copy number variants and multiple areas of homozygosity. Recessive genes in these regions were examined to identify any compatible with the patient’s phenotype. Testing for variants in these genes was negative. Exome sequencing was then ordered in 2013, revealing multiple variants of uncertain significance (VUSs) unlikely to be the cause of her neurological findings. Exome reanalysis in 2017 and 2019 were both negative. In 2019, she was diagnosed with dystonia. Because genes associated with dystonia were not included in the prior exome reanalysis, a comprehensive dystonia panel was ordered which was negative. Exome reanalysis was performed again in 2021 including the new symptoms. The laboratory reported a homozygous variant of uncertain significance (VUS) in SLC7A6OS, confirmed by Sanger sequencing, and seen in the heterozygous state in both parents. This is a novel variant predicted to be damaging/probably damaging in silico. The clinical manifestations of this patient correspond fully to the phenotype described in association with SLC7A6OS gene variants. Thus, we concluded that our patient most likely has EPM12. There is limited information on the phenotypic spectrum of EPM disease association with homozygous SLC7A6OS variants, with the first reported case published recently in 2021. We report a patient with this rare condition and symptoms consistent with the patients previously reported in the literature. The patient had a homozygous variant that the lab reported as a VUS. However, because of the strong phenotypic match and the in silico models predicting this variant to be damaging, we reported this variant as associated with EPM12. This case highlights the importance of trained genetic providers evaluating VUSs to correlate the pathogenicity evidence in cases where strong gene-disease associations overlap with the patient’s phenotype. Our case also demonstrates the clinical utility of updating patients’ phenotypes and repeating exome reanalysis every few years. Often, patients can be discouraged after multiple exome reanalyses fail to provide them with any answers. It is the responsibility of the genetic providers to educate their patients on how exome data is analyzed and the fact that future reanalysis may identify new genes associated with their phenotype. Using multiple exome reanalyses, we were able to identify a cause for this patient’s progressive neurological symptoms and resolve a 10-year diagnostic odyssey for the patient and her family. They can now use this information for future family planning and for providing the most appropriate surveillance and management for the patient.