Amplexa Genetics Research Contributions

Below is a chronological overview of the publications that Amplexa Genetics has contributed to. Use the menu on the left to look at individual contributions from Amplexa Genetics researchers and partners. 

Mutations in GABRB3: From febrile seizures to epileptic encephalopathies
Publication: Neurology. 2017 Jan 4. pii.

Møller RS, Wuttke TV, Helbig I, Marini C, Johannesen KM, Brilstra EH, Vaher U, Borggraefe I, Talvik I, Talvik T, Kluger G, Francois LL, Lesca G, de Bellescize J, Blichfeldt S, Chatron N, Holert N, Jacobs J, Swinkels M, Betzler C, Syrbe S, Nikanorova M, Myers CT, Larsen LH, Vejzovic S, Pendziwiat M, von Spiczak S, Hopkins S, Dubbs H, Mang Y, Mukhin K, Holthausen H, van Gassen KL, Dahl HA, Tommerup N, Mefford HC, Rubboli G, Guerrini R, Lemke JR, Lerche H, Muhle H, Maljevic S.

OBJECTIVE: To examine the role of mutations in GABRB3 encoding the β3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. METHODS: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. RESULTS: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant β3, together with α5and γ2s subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations. CONCLUSIONS: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism.
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Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy

Publication: Neurol Genet. 2016 Dec; 2(6): e118.

Authors: Møller RS, Weckhuysen S, Chipaux M, Marsan E, Taly V, Bebin EM, Hiatt SM, Prokop JW, Bowling KM, Mei D, Conti V, de la Grange P,Ferrand-Sorbets S, Dorfmüller G, Lambrecq V, Larsen LH, Leguern E, Guerrini R, Rubboli G, Cooper GM, Baulac S.


Objective: To assess the prevalence of somatic MTOR mutations in focal cortical dysplasia (FCD) and of germline MTOR mutations in a broad range of epilepsies. Methods: We collected 20 blood-brain paired samples from patients with FCD and searched for somatic variants using deep-targeted gene panel sequencing. Germline mutations in MTOR were assessed in a French research cohort of 93 probands with focal epilepsies and in a diagnostic Danish cohort of 245 patients with a broad range of epilepsies. Data sharing among collaborators allowed us to ascertain additional germline variants in MTOR. Results: We detected recurrent somatic variants (p.Ser2215Phe, p.Ser2215Tyr, and p.Leu1460Pro) in the MTOR gene in 37% of participants with FCD II and showed histologic evidence for activation of the mTORC1 signaling cascade in brain tissue. We further identified 5 novel de novo germline missense MTOR variants in 6 individuals with a variable phenotype from focal, and less frequently generalized, epilepsies without brain malformations, to macrocephaly, with or without moderate intellectual disability. In addition, an inherited variant was found in a mother–daughter pair with nonlesional autosomal dominant nocturnal frontal lobe epilepsy. Conclusions: Our data illustrate the increasingly important role of somatic mutations of the MTOR gene in FCD and germline mutations in the pathogenesis of focal epilepsy syndromes with and without brain malformation or macrocephaly.

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Association between genes on chromosome 19p13.2 and panic disorder.

Publication: Psychiatr Genet. 2016 Dec;26(6):287-292.

Authors: Gregersen NO, Buttenschøn HN, Hedemand A, Nielsen MN, Dahl HA, Kristensen AS, Johansen O, Woldbye DP, Erhardt A, Kruse TA, Wang AG, Børglum AD, Mors O. 


Panic disorder (PD) is a severe and disabling mental disorder, which is moderately heritable. In a previous study, we carried out a genome-wide association study using patients with PD and control individuals from the isolated population of the Faroe Islands and identified chromosome 19p13.2 as a candidate region. To further investigate this chromosomal region for association with PD, we analysed eight single nucleotide polymorphisms (SNPs) in three candidate genes - small-nuclear RNA activating complex, polypeptide 2 (SNAPC2), mitogen-activated protein kinase kinase 7 (MAP2K7) and leucine-rich repeat containing 8 family, member E (LRRC8E) - these genes have previously been directly or indirectly implicated in other mental disorders. A total of 511 patients with PD and 1029 healthy control individuals from the Faroe Islands, Denmark and Germany were included in the current study. SNPs covering the gene region of SNAPC2, MAP2K7 and LRRC8E were genotyped and tested for association with PD. In the Faroese cohort, rs7788 within SNAPC2 was significantly associated with PD, whereas rs3745383 within LRRC8E was nominally associated. No association was observed between the analysed SNPs and PD in the Danish cohorts. In the German women, we observed a nominal association between rs4804833 within MAP2K7 and PD. We present further evidence that chromosome 19p13.2 may harbour candidate genes that contribute towards the risk of developing PD. Moreover, the implication of the associated genes in other mental disorders may indicate shared genetic susceptibility between mental disorders. We show that associated variants may be sex specific, indicating the importance of carrying out a sex-specific association analysis of PD.

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Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies.

Publcation: Neurology. 2016 Sep 13;87(11):1140-51.

Authors: Johannesen K, Marini C, Pfeffer S, Møller RS, Dorn T, Niturad C, Gardella E, Weber Y, Søndergård M, Hjalgrim H, Nikanorova M, Becker F, Larsen LH, Dahl HA, Maier O, Mei D, Biskup S, Klein KM, Reif PS, Rosenow F, Elias AF, Hudson C, Helbig KL, Schubert-Bast S, Scordo MR, Craiu D, Djémié T, Hoffman-Zacharska D, Caglayan H, Helbig I, Serratosa J, Striano P, De Jonghe P, Weckhuysen S, Suls A, Muru K, Talvik I, Talvik T, Muhle H, Borggraefe I, Rost I, Guerrini R, Lerche H, Lemke JR, Rubboli G, Maljevic S.


Objective: To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients withGABRA1 gene mutations. Methods: Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected. Functional analysis of 4 selected mutations was performed using the Xenopus laevis oocyte expression system. Results: The study included 16 novel probands and 3 additional family members with a disease-causing mutation in the GABRA1 gene. The phenotypic spectrum varied from unspecified epilepsy (1), juvenile myoclonic epilepsy (2), photosensitive idiopathic generalized epilepsy (1), and generalized epilepsy with febrile seizures plus (1) to severe epileptic encephalopathies (11). In the epileptic encephalopathy group, the patients had seizures beginning between the first day of life and 15 months, with a mean of 7 months. Predominant seizure types in all patients were tonic-clonic in 9 participants (56%) and myoclonic seizures in 5 (31%). EEG showed a generalized photoparoxysmal response in 6 patients (37%). Four selected mutations studied functionally revealed a loss of function, without a clear genotype–phenotype correlation. Conclusions: GABRA1 mutations make a significant contribution to the genetic etiology of both benign and severe epilepsy syndromes. Myoclonic and tonic-clonic seizures with pathologic response to photic stimulation are common and shared features in both mild and severe phenotypes.

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Gene panel testing in epileptic encephalopathies and familial epilepsies.

Publication: Mol Syndromol. 2016 Sep;7(4):210-219.

Authors: Møller RS, Larsen LHG, Johannesen KM, Talvik, Talvik T, Vaher U, Miranda MJ, Farooq M, Nielsen JEK, Lavard Svendsen L, Kjelgaard DB, Linnet KM, Hao Q, Uldall P,, Frangu M, Tommerup N, Baig SM, Abdullah U, Born AP, Gellert P, Nikanorova M, Olofsson K, Jepsen B, Marjanovic D, Al-Zehhawi LIK, Peñalva SJ, Krag-Olsen B, Brusgaard K, Hjalgrim H, Rubboli G, Pal DK, Dahl HA. 


Abstract: In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including SCN1A, STXBP1, CDKL5, SCN2A, SCN8A, GABRA1, KCNA2, and STX1B. Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.

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PKD_Not always nomina sunt consequentia rerum.ays nomina sunt consequentia rerum.

Publication: Annals of Neurology, 2016 Apr 21.

Authors: Gardella E, Beniczky S, Møller RS, Becker F, Lemke JR, Syrbe S, Eiberg H, Bast T, Steinhoff B, Nürnberg P, Gellert P, Dahl HA, Weckhuysen S, Heron S, Dibbens L, Hjalgrim H, Lerche H, Weber YG.

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Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation.

Publication: Ann Neurol. 2016 Mar;79(3):428-36.

Authors: Gardella E, Becker F, Møller RS, Schubert J, Lemke JR, Larsen LH, Eiberg H, Nothnagel M, Thiele H, Altmüller J, Syrbe S, Merkenschlager A, Bast T, Steinhoff B, Nürnberg P, Mang Y, Bakke Møller L, Gellert P, Heron SE, Dibbens LM, Weckhuysen S, Dahl HA, Biskup S, Tommerup N, Hjalgrim H, Lerche H, Beniczky S, Weber YG.


Abstract: OBJECTIVE: Benign familial infantile seizures (BFIS), paroxysmal kinesigenic dyskinesia (PKD), and their combination-known as infantile convulsions and paroxysmal choreoathetosis (ICCA)-are related autosomal dominant diseases. PRRT2 (proline-rich transmembrane protein 2 gene) has been identified as the major gene in all 3 conditions, found to be mutated in 80 to 90% of familial and 30 to 35% of sporadic cases. METHODS: We searched for the genetic defect in PRRT2-negative, unrelated families with BFIS or ICCA using whole exome or targeted gene panel sequencing, and performed a detailed cliniconeurophysiological workup. RESULTS: In 3 families with a total of 16 affected members, we identified the same, cosegregating heterozygous missense mutation (c.4447G>A; p.E1483K) in SCN8A, encoding a voltage-gated sodium channel. A founder effect was excluded by linkage analysis. All individuals except 1 had normal cognitive and motor milestones, neuroimaging, and interictal neurological status. Fifteen affected members presented with afebrile focal or generalized tonic-clonic seizures during the first to second year of life; 5 of them experienced single unprovoked seizures later on. One patient had seizures only at school age. All patients stayed otherwise seizure-free, most without medication. Interictal electroencephalogram (EEG) was normal in all cases but 2. Five of 16 patients developed additional brief paroxysmal episodes in puberty, either dystonic/dyskinetic or "shivering" attacks, triggered by stretching, motor initiation, or emotional stimuli. In 1 case, we recorded typical PKD spells by video-EEG-polygraphy, documenting a cortical involvement. INTERPRETATION: Our study establishes SCN8A as a novel gene in which a recurrent mutation causes BFIS/ICCA, expanding the clinical-genetic spectrum of combined epileptic and dyskinetic syndromes.

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The contribution of next generation sequencing to epilepsy genetics.

Publication: Expert Review of Molecular Diagnostics, October 2015;15(12):1531-8

Authors: Møller RS, Dahl HA, Helbig I. 


Abstract: During the last decade, next generation sequencing technologies such as targeted gene panels, whole exome sequencing and whole genome sequencing have led to an explosion of gene identifications in monogenic epilepsies including both familial epilepsies and severe epilepsies, often referred to as epileptic encephalopathies. The increased knowledge about causative genetic variants has had a major impact on diagnosis of genetic epilepsies and has already been translated into treatment recommendations for a few genes. This article provides an overview of how next generation sequencing has advanced our understanding of epilepsy genetics and discusses some of the recently discovered genes in monogenic epilepsies.

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Mutations in KCNT1 cause a spectrum of focal epilepsies

Publication: Epilepsia. 2015 Sep;56(9):114-20

Authors: Møller RS, Heron SE, Larsen LH, Lim CX, Ricos MG, Bayly MA, van Kempen MJ, Klinkenberg S, Andrews I, Kelley K, Ronen GM, Callen D, McMahon JM, Yendle SC, Carvill GL, Mefford HC, Nabbout R, Poduri A, Striano P, Baglietto MG, Zara F, Smith NJ, Pridmore C, Gardella E, Nikanorova M, Dahl HA, Gellert P, Scheffer IE, Gunning B, Kragh-Olsen B, Dibbens LM. 


Abstract: Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype-phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances.

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Clinical phenotype of GNAO1: Case report and Review of literature

Publication: Child Neurology Open, Vol. 2, No. 2 April - June 2015: 1-7

Authors: Talvik I,  Møller RS, Vaher M, Vaher U, Larsen LHG, Dahl HA, Ilves P, Talvik T.


Abstract: Mutations in the guanine nucleotide-binding protein (G protein), α activating activity polypeptide O (GNAO1) gene have recently been described in 6 patients with early infantile epileptic encephalopathies. In the present study, we report the phenotype and the clinical course of a 4-year-old female with an epileptic encephalopathy (Ohtahara syndrome) and profound intellectual disability due to a de novo GNAO1 mutation (c.692A>G; p.Tyr231Cys). Ohtahara syndrome is a devastating early infantile epileptic encephalopathy that can be caused by mutations in different genes, now also including GNAO1. The mutation was found using a targeted next generation sequencing gene panel and demonstrates targeted sequencing as a powerful tool for identifying mutations in genes where only a few de novo mutations have been identified.

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Are TMEM genes potential candidate genes for panic disorder?

Publication: Psychiatr Genet. 2014 Feb;24(1):37-41. 

Authors: Gregersen NO, Buttenschøn HN, Hedemand A, Dahl HA, Kristensen AS, Clementsen B, Woldbye DP, Koefoed P, Erhardt A, Kruse TA, Wang AG, Børglum AD, Mors O.


Abstract: We analysed single nucleotide polymorphisms in two transmembrane genes (TMEM98 and TMEM132E) in panic disorder (PD) patients and control individuals from the Faroe Islands, Denmark and Germany. The genes encode single-pass membrane proteins and are located within chromosome 17q11.2-q12, a previously reported candidate region for PD. Three single nucleotide polymorphisms (rs887231, rs887230 and rs4795942) located upstream and within TMEM132E showed a nominal significant association with PD primarily in the Danish cohort. No nominal significant associations were observed between TMEM98 and PD. Our data indicate that TMEM132E might contribute moderately towards the risk of developing PD.

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The role of SLC2A1 in early onset and childhood absence epilepsies

Publication: Epilepsy Res. 2013 Jul;105(1-2):229-33.

Authors: Muhle H, Helbig I, Frøslev TG, Suls A, von Spiczak S, Klitten LL, Dahl HA, Brusgaard K, Neubauer B, De Jonghe P, Tommerup N, Stephani U, Hjalgrim H, Møller RS.


Abstract: Early Onset Absence Epilepsy constitutes an Idiopathic Generalized Epilepsy with absences starting before the age of four years. Mutations in SLC2A1, encoding the glucose transporter, account for approximately 10% of EOAE cases. The role of SLC2A1 mutations in absence epilepsies with a later onset has not been assessed. We found two mutation carriers in 26 EOAE patients, while no mutations were found in 124 probands affected by CAE or JAE.

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