Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-onset Epilepsy

Demos, Michelle; Guella, Ilaria; McKenzie, Michael; Buerki, Sarah E.; Evans, Daniel M.; Toyota, Eric B.; Boelman, Cyrus; Huh, Linda; Datta, Anita; Michoulas, Aspasia; Selby, Kathryn; Björnson, Bruce; Horváth, Gabriella; Lopez-Rangel, Elena; Salvarinova, Ramona; Slade, Erin; Eydoux, Patrice; Adam, Shelin; Allen, Margot I. Van; Nelson, Tanya N.; Bolbocean, Corneliu; Connolly, Mary; Farrer, Matthew J.

doi:10.1101/139329

Cited by 24 publications

(41 citation statements)

References 32 publications

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“…Patient 5 was enrolled in a study identifying new genetic causes of Rett syndrome‐like phenotypes, while patient 8 was diagnosed with SLC35A2‐CDG in research identifying genetic causes for cerebral visual impairment (CVI) . Patient 15 was diagnosed via research study EPGEN …”

Section: Methodsmentioning

confidence: 99%

Clinical, neuroradiological, and biochemical features of SLC35A2‐CDG patients

Vals

Ashikov

Ilves

et al. 2019

J of Inher Metab Disea

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SLC35A2-CDG is caused by mutations in the X-linked SLC35A2 gene encoding the UDP-galactose transporter. SLC35A2 mutations lead to hypogalactosylation of Nglycans. SLC35A2-CDG is characterized by severe neurological symptoms and, in many patients, early-onset epileptic encephalopathy. In view of the diagnostic challenges, we studied the clinical, neuroradiological, and biochemical features of 15 patients (11 females and 4 males) with SLC35A2-CDG from various centers. We describe nine novel pathogenic variations in SLC35A2. All affected individuals presented with a global developmental delay, and hypotonia, while 70% were nonambulatory. Epilepsy was present in 80% of the patients, and in EEG hypsarrhythmia and findings consistent with epileptic encephalopathy were frequently seen. The most common brain MRI abnormality was cerebral atrophy with delayed myelination and multifocal inhomogeneous abnormal patchy white matter hyperintensities, which seemed to be nonprogressive. Thin corpus callosum was also common, and all the patients had a corpus callosum shorter than normal for their age. Variable dysmorphic features and growth deficiency were noted. Biochemically, normal mucin type O-glycosylation and lipid glycosylation were found, while transferrin mass spectrometry was found to be more specific in the identification of SLC35A2-CDG, as compared to routine screening tests. Although normal glycosylation studies together with clinical variability and genetic results complicate the diagnosis of SLC35A2-CDG, our data indicate that the combination of these three elements can support the pathogenicity of mutations in SLC35A2. K E Y W O R D SCDG, congenital glycosylation disorders, epileptic encephalopathy, infantile spasms, SLC35A2

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Section: Methodsmentioning

confidence: 99%

Clinical, neuroradiological, and biochemical features of SLC35A2‐CDG patients

Vals

Ashikov

Ilves

et al. 2019

J of Inher Metab Disea

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“…43 Comparably, in 180 patients with childhood epilepsy who were previously undiagnosed, 33% received a molecular diagnosis through whole exome sequencing. 44 It is important to note that these studies largely involved people in whom typical evaluations (history, physical examination, and imaging) did not identify an etiology. Narrowing down the criteria to enrich for genetic causes of epilepsy results in a higher diagnosis rate.…”

Section: Providing a Diagnosismentioning

confidence: 99%

Genetic Testing in Epilepsy

Ritter

Holland

2020

Semin Neurol

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Because of next-generation sequencing and the discovery of many new causative genes, genetic testing in epilepsy patients has become widespread. Pathologic variants resulting in epilepsy cause a variety of changes that can be broadly classified into syndromic disorders (i.e., chromosomal abnormalities), metabolic disorders, brain malformations, and abnormal cellular signaling. Here, we review the available genetic testing, reasons to pursue genetic testing, common genetic causes of epilepsy, the data behind what patients are found to have genetic epilepsies based on current testing, and discussing these results with patients. We propose an algorithm for testing patients with epilepsy to maximize yield and limit costs based on their phenotype (including electroencephalography and magnetic resonance imaging findings), age of seizure onset, and presence of other neurologic comorbidities. Being able to discern which type of genetic testing to order, using that information to give targeted and cost-effective patient care, and interpreting results accurately will be a crucial skill for the modern neurologist.

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“…Trio-based exome sequencing was performed on DNA extracted from peripheral-blood lymphocytes with the Ion AmpliSeq Exome Kit (57.7 Mb) and Ion Proton System, and then genes linked or associated with seizure disorders underwent bioinformatics analysis and prioritization. 13 Variants were confirmed with Sanger sequencing. Primer sequences are available upon request.…”

Section: Introductionmentioning

confidence: 99%