Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies

Møller, Rikke S.; Larsen, Line H.G.; Johannesen, Katrine M; Talvik, Inga; Talvik, Tiina; Vaher, Ulvi; Miranda, María J; Farooq, Muhammad; Nielsen, Jens Erik; Svendsen, Lene Lavard; Kjelgaard, Ditte B; Linnet, Karen Markussen; Qin, Hao; Uldall, Peter; Frangu, Mimoza; Tommerup, Niels; Baig, Shahid Mahmood; Abdullah, Uzma; Born, Alfred Peter; Gellert, Pia; Nikanorova, Marina; Olofsson, Kern; Jepsen, Birgit; Marjanović, Dragan; Al-Zehhawi, Lana I K; Peñalva, Sofia J; Krag-Olsen, B; Brusgaard, Klaus; Hjalgrim, Helle; Rubboli, Guido; Pal, Deb K.; Dahl, Hans Atli

doi:10.1159/000448369

Cited by 103 publications

(123 citation statements)

References 68 publications

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“…SCN2A was the second most commonly implicated gene in our cohort, involved in 10 of 135 (7%) patients; 8 individuals have been previously reported . The 2 new individuals have recurrent pathogenic variants seen in patients with DEEs (p.E999K and p.V251I) but not in EIMFS (see Supplementary Table 2).…”

Section: Resultsmentioning

confidence: 99%

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

Burgess

Wang

McTague

et al. 2019

Annals of Neurology

106

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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

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Section: Resultsmentioning

confidence: 99%

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

Burgess

Wang

McTague

et al. 2019

Annals of Neurology

106

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“…Myoclonus in the absence of seizures was observed in one family with four affected family members. 28 It is likely that variations in other genes in the genetic background contribute to this variation; the effects of modifier genes on seizure phenotypes have been well established in the mouse. 10,14 On the other hand, absence epilepsy was observed in a family with the heterozygous protein truncating variant p.Asn544fs*39, 6 and focal epilepsy with mild ID was observed for the protein truncation variant p.Arg1820*0.…”

Section: Discussionmentioning

confidence: 99%

Biallelic inherited SCN8A variants, a rare cause of SCN8A‐related developmental and epileptic encephalopathy

Wengert

Tronhjem²,

Wagnon

et al. 2019

Epilepsia

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Objective: Monoallelic de novo gain-of-function variants in the voltage-gated sodium channel SCN8A are one of the recurrent causes of severe developmental and epileptic encephalopathy (DEE). In addition, a small number of de novo or inherited monoallelic loss-of-function variants have been found in patients with intellectual disability, autism spectrum disorder, or movement disorders. Inherited monoallelic variants causing either gain or loss-of-function are also associated with less severe conditions such as benign familial infantile seizures and isolated movement disorders. In all three categories, the affected individuals are heterozygous for a SCN8A variant in combination with a wild-type allele. In the present study, we describe two unusual families with severely affected individuals who inherited biallelic variants of SCN8A. Methods: We identified two families with biallelic SCN8A variants by diagnostic gene panel sequencing. Functional analysis of the variants was performed using voltage clamp recordings from transfected ND7/23 cells. Results: We identified three probands from two unrelated families with DEE due to biallelic SCN8A variants. Each parent of an affected individual carried a single heterozygous SCN8A variant and exhibited mild cognitive impairment without seizures. In both families, functional analysis demonstrated segregation of one allele with complete loss-of-function, and one allele with altered biophysical properties consistent with partial loss-of-function. Significance: These studies demonstrate that SCN8A DEE may, in rare cases, result from inheritance of two variants, both of which exhibit reduced channel activity. In these families, heterozygosity for the dominant variants results in less severe disease than biallelic inheritance of two variant alleles. The clinical consequences of variants 2278 | WENGERT ET al.

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“…Among the patients, without deficiencies in 1 of these 3 genes ( n = 35), pathogenic sequence variants were identified in SCN2A ( n = 1), STXBP1 ( n = 2) and TCF4 ( n = 1); all genes previously linked to Rett‐like phenotype (Table ), using different technologies including single gene or whole exome sequencing, and a previously described epilepsy gene panel . Notably, in one patient we identified a de novo variant in KCNB1 , which was not previously linked to Rett syndrome spectrum.…”

Section: Danish Cohort Of Rtt Atypical Rtt and Rett‐like Phenotypesmentioning

confidence: 91%

Clinician’s guide to genes associated with Rett‐like phenotypes—Investigation of a Danish cohort and review of the literature

et al. 2018

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The differential diagnostics in Rett syndrome has evolved with the development of next generation sequencing-based techniques and many patients have been diagnosed with other syndromes or variants in newly described genes where the associated phenotype(s) is yet to be fully explored. The term Rett-like refers to phenotypes with distinct overlapping features of Rett syndrome where the clinical criteria are not completely fulfilled. In this study we have combined a review of Rett-like disorders with data from a Danish cohort of 35 patients with Rett-like phenotypes emphasizing the diagnostic overlap with Pitt-Hopkins syndrome, Cornelia de Lange syndrome with SMC1A variants, and epileptic encephalopathies, for example, due to STXBP1 variants. We also found a patient with a pathogenic variant in KCNB1, which has not been previously linked to a Rett-like phenotype. This study underlines the clinical and genetic heterogeneity of a Rett syndrome spectrum, and provides an overview of the Rett syndrome-related genes described to date, and hence serves as a guide for diagnosing patients with Rett-like phenotypes.

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Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies

Cited by 103 publications

References 68 publications

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

Biallelic inherited SCN8A variants, a rare cause of SCN8A‐related developmental and epileptic encephalopathy

Clinician’s guide to genes associated with Rett‐like phenotypes—Investigation of a Danish cohort and review of the literature

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