De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy

Stringer, Robin N; Jurkovičová-Tarabová, Bohumila; Souza, Ivana A.; Ibrahim, Judy; Vacı́k, Tomáš; Fathalla, Waseem; Hertecant, Jozef; Zamponi, Gerald W.; Lacinová, Ľubica; Weiss, Norbert

doi:10.1186/s13041-021-00838-y

Cited by 6 publications

(5 citation statements)

References 19 publications

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“…Stringer and others recently described a patient with epileptic encephalopathy who harbors a de novo heterozygous in-frame duplication in SCN8A (p.G1625_I1627dup) and an inherited heterozygous missense variant in CACNA1H (p.G318S) ( Stringer et al, 2021 ). The p.G1625_I1627dup variant ( Figure 1A , blue circle), located in the DIVS4 transmembrane domain, is proximal to several pathogenic variants, including p.R1620L ( Rossi et al, 2017 ; Liu et al, 2019 ) and p.A1622D ( Liu et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, while this duplication does not overlap with the amino acids altered in the ΔIRL and ΔVIR mice, it is immediately adjacent to them ( Figure 1B ). The p.G1625_I1627dup variant resulted in a hyperpolarizing shift of the voltage-dependence of activation of Na v 1.6 but had no effect on sodium current density or gating mechanisms ( Stringer et al, 2021 ). This observation is consistent with a gain-of-function effect on the Na v 1.6 channel; however, Stringer et al also demonstrated that the c.952G > A, p.G318S variant in CACNA1H was associated with loss-of-function effects.…”

Section: Discussionmentioning

confidence: 99%

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Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease

et al. 2021

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Numerous SCN8A mutations have been identified, of which, the majority are de novo missense variants. Most mutations result in epileptic encephalopathy; however, some are associated with less severe phenotypes. Mouse models generated by knock-in of human missense SCN8A mutations exhibit seizures and a range of behavioral abnormalities. To date, there are only a few Scn8a mouse models with in-frame deletions or insertions, and notably, none of these mouse lines exhibit increased seizure susceptibility. In the current study, we report the generation and characterization of two Scn8a mouse models (ΔIRL/+ and ΔVIR/+) carrying overlapping in-frame deletions within the voltage sensor of domain 4 (DIVS4). Both mouse lines show increased seizure susceptibility and infrequent spontaneous seizures. We also describe two unrelated patients with the same in-frame SCN8A deletion in the DIV S5-S6 pore region, highlighting the clinical relevance of this class of mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease

et al. 2021

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“…Another homozygous mutation was observed in one individual for a missense mutation in Calcium Voltage-Gated Channel Subunit Alpha1 H (CACNA1H) with three additional individuals also carrying one copy of this mutation. Mutations in this gene have been associated with generalized and severe epilepsies [ 33 , 34 ], although it has been debated whether this is a bona fide monogenic epilepsy gene [ 35 ]. This female individual was diagnosed with epilepsy at 15 years of age and does not have any other family members with a diagnosis of epilepsy, or any consanguinity noted.…”

Section: Resultsmentioning

confidence: 99%

Whole‐exome sequencing of a Saudi epilepsy cohort reveals association signals in known and potentially novel loci

Anazi

Ammar

Al-Hajj³

et al. 2022

Hum Genomics

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Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia, the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity among large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known epilepsy-related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline-based variant prioritization approach in an attempt to discover putative causative variants. We identified 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity was observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants in known epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci which may be prioritized for further investigation.

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“…Moreover, an inherited CACNA1H variant has already been reported in worsening a DEE phenotype in association with another gene [ 71 ].…”

Section: Discussionmentioning

confidence: 99%

The Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge

Musante

Costa

Zanus

et al. 2022

Genes

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Epileptic encephalopathies (EEs) and developmental and epileptic encephalopathies (DEEs) are a group of severe early-onset neurodevelopmental disorders (NDDs). In recent years, next-generation equencing (NGS) technologies enabled the discovery of numerous genes involved in these conditions. However, more than 50% of patients remained undiagnosed. A major obstacle lies in the high degree of genetic heterogeneity and the wide phenotypic variability that has characterized these disorders. Interpreting a large amount of NGS data is also a crucial challenge. This study describes a dynamic diagnostic procedure used to investigate 17 patients with DEE or EE with previous negative or inconclusive genetic testing by whole-exome sequencing (WES), leading to a definite diagnosis in about 59% of participants. Biallelic mutations caused most of the diagnosed cases (50%), and a pathogenic somatic mutation resulted in 10% of the subjects. The high diagnostic yield reached highlights the relevance of the scientific approach, the importance of the reverse phenotyping strategy, and the involvement of a dedicated multidisciplinary team. The study emphasizes the role of recessive and somatic variants, new genetic mechanisms, and the complexity of genotype–phenotype associations. In older patients, WES results could end invasive diagnostic procedures and allow a more accurate transition. Finally, an early pursued diagnosis is essential for comprehensive care of patients, precision approach, knowledge of prognosis, patient and family planning, and quality of life.

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De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy

Cited by 6 publications

References 19 publications

Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease

Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease

Whole‐exome sequencing of a Saudi epilepsy cohort reveals association signals in known and potentially novel loci

The Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge

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