Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies

Abstract

Objective We investigated the contribution to sporadic focal epilepsies (FE) of ultrarare variants in genes coding for the components of complexes regulating mechanistic Target Of Rapamycin (mTOR)complex 1 (mTORC1). Methods We collected genetic data of 121 Italian isolated FE cases and 512 controls by Whole Exome Sequencing (WES) and single‐molecule Molecular Inversion Probes (smMIPs) targeting 10 genes of the GATOR1, GATOR2, and TSC complexes. We collapsed “qualifying” variants (ultrarare and predicted to be deleterious or loss of function) across the examined genes and sought to identify their enrichment in cases compared to controls. Results We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in FE patients (P = 0.006; exact unconditional test, one‐tailed). Pathogenic variants were identified in DEPDC5 and TSC2, both major genes for Mendelian FE syndromes. Interpretation Our findings support the contribution of ultrarare variants in genes in the mTOR pathway complexes GATOR and TSC to the risk of sporadic FE and a shared genetic basis between rare and common epilepsies. The identification of a monogenic etiology in isolated cases, most typically encountered in clinical practice, may offer to a broader community of patients the perspective of precision therapies directed by the underlying genetic cause.

Sleep-related hypermotor epilepsy (SHE): Contribution of known genes in 103 patients

“…We found four loss-of-function variants in DEPDC5 (3.9 %, CI: 1.1-9.7 %): one novel frameshift (p.Thr381Hisfs*15) was detected in a sporadic case (Fig. 1B, pedigree 5), while the remaining (p.Arg389-Profs*2, p.Arg422*, c.193 + 1G > A) have been already published (Table 1) [11,12]. Interestingly, three of these patients have FCD.…”

Sleep-Related Hypermotor Epilepsy: Etiology, Electro-Clinical Features, and Therapeutic Strategies

“…The DEPDC5 variants identified include four LOF variants, namely, p.Arg389Profs*2, p.Arg422*c.193+1G>A, and p. Thr409Hisfs*15. 33,34 Furthermore, variants of the genes encoding NPRL2 and NPRL3 were also confirmed, but whether these mutations are pathogenic and their role in the pathogenesis of SHE still needs to be confirmed in further studies. [33][34][35] In addition to the aforementioned mutations, an Italian ADSHE family line study revealed a mutation in the CRH gene.…”

“…33,34 Furthermore, variants of the genes encoding NPRL2 and NPRL3 were also confirmed, but whether these mutations are pathogenic and their role in the pathogenesis of SHE still needs to be confirmed in further studies. [33][34][35] In addition to the aforementioned mutations, an Italian ADSHE family line study revealed a mutation in the CRH gene. 36 In 2013, Sansoni et al reported a novel mutation (p.Pro30Arg) within the CRH gene cosegregating with ADSHE d detected in an Italian family.…”

Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer’s disease and longevity in an Italian population

“…A nominal p value ≤0.01 was considered significant. Rare variant distribution within cases and controls was tested with a CMC (collapsing and combine) test as described elsewhere [56]. We defined qualifying variants as PASS variants with HIGH (stopgain, frameshift indels, canonical splicing) and MEDIUM (missense CADD>15) impact, with a MAF<1% in the ExAC database and never observed in the homozygous state in the GnomAD database.…”