Somatic <i>SLC35A2</i> variants in the brain are associated with intractable neocortical epilepsy

Winawer, Melodie R.; Griffin, Nicole G.; Samanamud, Jorge; Baugh, Evan H.; Rathakrishnan, Dinesh; Ramalingam, Senthilmurugan; Zagzag, David; Schevon, Catherine A.; Dugan, Patricia; Hegde, Manu; Sheth, Sameer A.; McKhann, Guy M.; Doyle, Werner; Grant, Gerald A.; Porter, Brenda E.; Mikati, Mohamad A.; Muh, Carrie R.; Malone, Colin D.; Bergin, Ann M.; Peters, Jurriaan M.; McBrian, Danielle; Pack, Alison; Akman, Cigdem I.; LaCoursiere, Christopher M.; Keever, Katherine M.; Madsen, Joseph R.; Yang, Edward; Lidov, Hart G.W.; Shain, Catherine; Allen, Andrew S.; Canoll, Peter; Crino, Peter B.; Poduri, Annapurna; Heinzen, Erin L.

doi:10.1002/ana.25243

Cited by 99 publications

(102 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We identified 2 probands with mosaic variants in SCN2A and GABRB3 causing EIMFS; they were as severely affected as patients with germline variants. For some diseases, the percentage mosaicism of a pathogenic variant correlates with disease severity; however, our patients had profound impairment. Potential variability in percentage mosaicism between tissues, such as brain and blood, has been hypothesized to explain these differences.…”

Section: Discussionmentioning

confidence: 99%

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

Burgess

Wang

McTague

et al. 2019

Annals of Neurology

Self Cite

109

View full text Add to dashboard Cite

Objective Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and genotype–phenotype correlations of a large EIMFS cohort. Methods Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study. Results We ascertained 135 patients from 128 unrelated families. Ninety‐three of 135 (69%) had causative variants (42/55 previously reported) across 23 genes, including 9 novel EIMFS genes: de novo dominant GABRA1, GABRB1, ATP1A3; X‐linked CDKL5, PIGA; and recessive ITPA, AIMP1, KARS, WWOX. The most frequently implicated genes were KCNT1 (36/135, 27%) and SCN2A (10/135, 7%). Mosaicism occurred in 2 probands (SCN2A, GABRB3) and 3 unaffected mothers (KCNT1). Median age at seizure onset was 4 weeks, with earlier onset in the SCN2A, KCNQ2, and BRAT1 groups. Epileptic spasms occurred in 22% patients. A total of 127 patients had severe to profound developmental impairment. All but 7 patients had ongoing seizures. Additional features included microcephaly, movement disorders, spasticity, and scoliosis. Mortality occurred in 33% at median age 2 years 7 months. Interpretation We identified a genetic cause in 69% of patients with EIMFS. We highlight the genetic heterogeneity of EIMFS with 9 newly implicated genes, bringing the total number to 33. Mosaicism was observed in probands and parents, carrying critical implications for recurrence risk. EIMFS pathophysiology involves diverse molecular processes from gene and protein regulation to ion channel function and solute trafficking. ANN NEUROL 2019;86:821–831

show abstract

Section: Discussionmentioning

confidence: 99%

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

Burgess

Wang

McTague

et al. 2019

Annals of Neurology

Self Cite

109

View full text Add to dashboard Cite

show abstract

“…This phenomenon is illustrated by one of our patients, who presented with infantile spasms, severe ID, and a right frontotemporal lesion that was eventually resected. A pathogenic somatic SLC35A2 variant was identified using deep sequencing in brain tissue; the variant was undetectable in our WES analysis of leukocyte‐derived DNA.…”

Section: Discussionmentioning

confidence: 94%

“…Apart from structural genetic variations, routine WES analysis, particularly in the clinical setting, may also not detect somatic variants in the brain. Somatic mutation is a recognized cause for neurodevelopmental disorders, both with and without evidence of a lesion on neuroimaging . Somatic variants that have arisen early in postzygotic development may be detectable in DNA obtained from blood leukocytes, but those that have arisen later will be undetectable in blood and rather require high‐depth sequencing of DNA derived from affected brain tissue.…”

Section: Discussionmentioning

confidence: 99%

Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort

et al. 2020

Self Cite

View full text Add to dashboard Cite

Objective We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well‐phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology. Methods We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection‐related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing. Results Overall, we identified pathogenic or likely pathogenic variants in 40% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy‐related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25%). Significance Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well‐phenotyped patients with epilepsy leads to a broader understanding of gene‐specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease‐associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.

show abstract

“…This might be explained by hepatocytes carrying the mutant allele being selected against during infancy . This might also be the reason why newly identified patients with intractable epilepsy with normal serum transferrin profiles showed mutations in resected brain specimens that were absent from leukocytes …”

Section: Discussionmentioning

confidence: 99%

“…21 This might also be the reason why newly identified patients with intractable epilepsy with normal serum transferrin profiles showed mutations in resected brain specimens that were absent from leukocytes. 22 It is important to mention the possible influence of genes other than those responsible for the disease that could influence the clinical characteristics of our cohort of patients. In fact, it has been recently proposed that common variants identified in the general population act as modifiers in PMM2-CDG, 23 highlighting the idea that the severity of a disease could depend on the genetic background of each particular patient.…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular diagnosis of non‐phosphomannomutase 2 N‐linked congenital disorders of glycosylation in Spain

et al. 2019

View full text Add to dashboard Cite

The congenital disorders of glycosylation (CDG) are defects in glycoprotein and glycolipid glycan synthesis and attachment. They affect multiple organ/systems, but non‐specific symptoms render the diagnosis of the different CDG very challenging. Phosphomannomutase 2 (PMM2)‐CDG is the most common CDG, but advances in genetic analysis have shown others to occur more commonly than previously thought. The present work reports the clinical and mutational spectrum of 25 non‐PMM2 CDG patients. The most common clinical symptoms were hypotonia (80%), motor or psychomotor disability (80%) and craniofacial dysmorphism (76%). Based on their serum transferrin isoform profile, 18 were classified as CDG‐I and 7 as CDG‐II. Pathogenic variations were found in 16 genes (ALG1, ALG6, ATP6V0A2, B4GALT1, CCDC115, COG7, DOLK, DPAGT1, DPM1, GFPT1, MPI, PGM1, RFT1, SLC35A2, SRD5A3, and SSR4). Overall, 27 variants were identified, 12 of which are novel. The results highlight the importance of combining genetic and biochemical analyses for the early diagnosis of this heterogeneous group of disorders.

show abstract

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy

Cited by 99 publications

References 55 publications

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort

Clinical and molecular diagnosis of non‐phosphomannomutase 2 N‐linked congenital disorders of glycosylation in Spain

Contact Info

Product

Resources

About