Somatic SLC35A2 mosaicism correlates with clinical findings in epilepsy brain tissue

Abstract

ObjectiveMany genetic studies of intractable epilepsy in pediatric patients primarily focus on inherited, constitutional genetic deficiencies identified in patient blood. Recently, studies have revealed somatic mosaicism associated with epilepsy in which genetic variants are present only in a subset of brain cells. We hypothesize that tissue-specific, somatic mosaicism represents an important genetic etiology in epilepsy and aim to discover somatic alterations in epilepsy-affected brain tissue.MethodsWe have pursued a research study to identify brain somatic mosaicism, using next-generation sequencing (NGS) technologies, in patients with treatment refractory epilepsy who have undergone surgical resection of affected brain tissue.ResultsWe used an integrated combination of NGS techniques and conventional approaches (radiology, histopathology, and electrophysiology) to comprehensively characterize multiple brain regions from a single patient with intractable epilepsy. We present a 3-year-old male patient with West syndrome and intractable tonic seizures in whom we identified a pathogenic frameshift somatic variant in SLC35A2, present at a range of variant allele fractions (4.2%–19.5%) in 12 different brain tissues detected by targeted sequencing. The proportion of the SLC35A2 variant correlated with severity and location of neurophysiology and neuroimaging abnormalities for each tissue.ConclusionsOur findings support the importance of tissue-based sequencing and highlight a correlation in our patient between SLC35A2 variant allele fractions and the severity of epileptogenic phenotypes in different brain tissues obtained from a grid-based resection of clinically defined epileptogenic regions.

Frequent SLC35A2 brain mosaicism in mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE)

“…Missense variants (30%) and in-frame insertions/deletions (4%) were considered as likely pathogenic based on in silico pathogenicity prediction, protein domain localization, amino acid conservation among species, absence from the gnomAD database and their presence at mosaic state in the lesional tissue. The variants p.Ser212Leu fs *9, p.Leu120His fs *7 and p.Gln185* were recurrent somatic variants; p.Ser212Leu fs *9 was previously reported in two other sporadic cases with focal epilepsy related to MCD [ 25 , 41 ]. SLC35A2 variant allele frequencies (VAFs) ranged from 1.4 to 52% among the cases.…”

“…Brain mosaic variants in genes belonging to the mechanistic Target of Rapamycin (mTOR) pathway have been discovered as underlying cause of FCD type 2 [ 2 , 8 , 21 , 26 , 39 ]. Recently, mosaic variants in the SLC35A2 gene, encoding the major Golgi‐localized UDP‐galactose transporter required for protein and sphingolipid glycosylation, have been identified in various forms of non-lesional focal epilepsies, as well as FCD type 1 and mMCD [ 2 , 25 , 38 , 39 , 41 ]. Moreover, germline de novo variants of SLC35A2 cause a rare X-linked dominant form of congenital disorder of glycosylation (CDG) type IIm (MIM #300896), primarily presenting with epileptic encephalopathy, seizures, severe psychomotor developmental delay and delayed myelination [ 30 , 40 ].…”

What does a defect in N-glycosylation mean for neuronal migration and function?

“…This lends some explanation for the surprisingly low (15%) yield of genetic testing of a peripheral DNA in this patient population. 9 A report by Miller et al 8 further validates the SLC35A2 gene as causal in FCD type 1 and lends support to experimental data linking disordered N-glycosylation to FCD type 1 and neuronal hyperexcitability and seizures. 10 It also attempts to link clinical markers of neuronal hyperexcitability to the burden of SLC35A2 variation.…”

“…Rather, it poses a research opportunity for the future. In summary, the case report by Miller et al 8 adds to the growing recognition of brain-restricted somatic mosaicism as causal to infantile spasms and NAFE. It provides additional evidence connecting the SLC35A2 gene to FCD type 1, thus opening opportunities to study glycosylation pathways in relationship to malformations of cortical development.…”

“…A defect in the UGT results in a reduced galactosylation of N-glycosylated proteins, glycosphingolipids, and proteoglycans, which affects neuronal migration, axon guidance, and synaptic physiology. 7 In this issue of Neurology ® Genetics, Miller et al,8 attempted to explore the impact of SLC35A2 gene insufficiency on neuronal excitability. Evaluation of a 3-year-old boy with West syndrome and generalized spasms showed that the ictal electrographic correlates demonstrated a consistent emphasis over the left posterior head quadrant, a region further implicated by a subtle signal abnormality on brain MRI and a hypometabolism on a fluorodeoxyglucose positron emission tomography.…”