Inclusion of hemimegalencephaly into the phenotypic spectrum of NPRL3 pathogenic variants in familial focal epilepsy with variable foci

Abstract

Despite tremendous progress through next generation sequencing technologies, familial focal epilepsies are insufficiently understood. We sought to identify the genetic basis in multiplex Palestinian families with familial focal epilepsy with variable foci (FFEVF). Family I with 10 affected individuals and Family II with five affected individuals underwent detailed phenotyping over three generations. The phenotypic spectrum of the two families varied from nonlesional focal epilepsy including nocturnal frontal lobe epilepsy to severe structural epilepsy due to hemimegalencephaly. Whole‐exome sequencing and single nucleotide polymorphism array analysis revealed pathogenic variants in NPRL3 in each family, a partial ~38‐kb deletion encompassing eight exons (exons 8‐15) and the 3′‐untranslated region of the NPRL3 gene in Family I, and a de novo nonsense variant c.1063C>T, p.Gln355* in Family II. Furthermore, we identified a truncating variant in the PDCD10 gene in addition to the NPRL3 variant in a patient with focal epilepsy from Family I. The individual also had developmental delay and multiple cerebral cavernomas, possibly demonstrating a digenic contribution to the individual's phenotype. Our results implicate the association of NPRL3 with hemimegalencephaly, expanding the phenotypic spectrum of NPRL3 in FFEVF and underlining that partial deletions are part of the genotypic spectrum of NPRL3 variants.

Epilepsy in the mTORopathies: opportunities for precision medicine

“… 11 FCD type II is the most common MCD seen in GATOR1-related epilepsies. 9–11 , 30 , 61 , 63 FCD type I, 11 , 30 , 36 BOSD, 26 , 61 , 121 HME, 31 , 122 polymicrogyria 4 and subcortical band heterotopia 121 have also been reported in individuals with GATORopathies ( Table 3 ). Cognitive comorbidities are seen in approximately half of affected individuals and psychiatric disorders observed in over 40% of cases.…”

DataSheet1.PDF

“…The proposed pathogenic mechanism of the NPRL3 gene mutation is that LOF causes an haploinsufficiency induced by nonsense-mediated decay of mRNA as previously suggested that truncating mutations in NPRL3 reduce transcript levels significantly (Canavati et al, 2019). In this study, we found a nonsense mutation c.316C>T, p. Gln106* in the NPRL3 gene, which is located in exon4 (Figure 2).…”

NPRL3: Direct Effects on Human Phenotypic Variability, mTOR Signaling, Subcellular mTOR Localization, Cortical Lamination, and Seizure Susceptibility

“…For example, some NPRL3 c.349delG heterozygotes develop seizures, while others will not (overall, seizure penetrance was estimated at 28%). In patients with epilepsy, MRI findings revealed a spectrum ranging from no visible abnormalities to hemimegalencephaly, ours being the second reported case of hemimegalencephaly associated with a pathogenic NPRL3 variant 9 . Surprisingly, the most severe seizure phenotypes were not always observed in patients with the most abnormal MRIs and in some individuals with seizures, brain MRI was normal.…”

“…Focal cortical dysplasia II (FCDII) is an MCD highly associated with intractable seizures defined by disorganized cerebral cortical lamination, enlarged (cytomegalic) dysmorphic neurons, and heterotopic neurons in the white matter 3 . Variants in genes encoding components of the GTPase Activating Protein (GAP) Activity Towards Rags Complex 1 (GATOR1), including DEP domain containing 5 (DEPDC5), Nitrogen Permease Regulator Like 2 (NPRL2), and Nitrogen Permease Regulator Like 3 (NPRL3) [4][5][6] , are the most common MPG variants associated with FCDII 7 and hemimegalencephaly (HME), a MCD defined by a hemispheric enlargement and FCD-type II histopathology 8,9 .…”

“…GATOR1 subunits are highly expressed in brain 13,14 and the effects of for example, DEPDC5 variants on cell size, motility, and firing as well as cortical lamination have been shown in several experimental models [15][16][17][18][19][20] and in human brain specimens 4,7 . While human tissue studies show a link between NPRL3 variants and mTOR activation 9,[21][22][23] , surprisingly few studies have investigated the role of NPRL3 in neuronal morphology, cortical lamination, and cortical circuitry.…”