Identifikation genetischer Ursachen familiärer Epilepsien im Mittleren Osten

• Antragsteller: Professor Dr. Ingo Helbig
• Fachliche Zuordnung: Molekulare und zelluläre Neurologie und Neuropathologie
• Förderung: Förderung von 2014 bis 2019
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 245609332

• Erstellungsjahr: 2019

Zusammenfassung der Projektergebnisse

In summary, the current project performed genetic studies in 119 families affected by epilepsy and neurodevelopmental disorders in Israel and Palestine, including 873 individuals. We identified a monogenic cause in 16/119 families (13,4%), a percentage that was lower than typically seen in large family studies where the diagnostic yield may be up to 30%. Only two genes (SCN1A, KCNQ2) were seen as causative genetic etiologies in more than one family, underlining the genetic heterogeneity in this cohort. Polygenic risk scores failed to translate into our study cohort given the population differences, suggesting that novel strategies are required to assess the contribution of common genetic variants in small pedigrees. Taking together, more than 80% of the familial risk of epilepsy remains unexplained despite state-of-the-art genetic analysis, including analysis of novel genetic etiologies in some individuals. Several novel genetic etiologies including KCNB1, ARHGEF9, and NPRL3 were supported by finding in our current cohort. Our study highlights the role of known monogenic causes in familial epilepsies, emphasizes the need for ongoing gene discovery, and indicates a persisting major gap in explaining the familial risk for epilepsies, even in the presence of genomic information. We aim to extend our studies to include novel methods to analysis complex genetic contributions in families including computational methods for genotype-phenotype correlations, and apply novel genetic analysis techniques including genome sequencing and repeat expansions in the continuation of the current project.

Projektbezogene Publikationen (Auswahl)

• Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures. Am J Hum Genet 2015;96:808-15
  Carvill GL, McMahon JM, …; EuroEPINOMICS Rare Epilepsy Syndrome Myoclonic-Astatic Epilepsy & Dravet working group, Helbig I, Striano P, Weckhuysen S, Berkovic SF, Scheffer IE, Mefford HC
  
• The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome. Epilepsia 2015;56:e203-8
  Larsen J, Johannesen KM, …; MAE working group of EuroEPINOMICS RES Consortium, …, Helbig I, Møller RS
  
• A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia. Ann Neurol. 2016 Oct;80(4)
  Helbig KL, Hedrich UB, …, Helbig I, Lerche H, Lemke JR
  
• Autosomal dominant epilepsy with auditory features: a new LGI1 family including a phenocopy with cortical dysplasia. J Neurol. 2016 Jan;263(1):11-6
  Klein KM, Pendziwiat M, …, Afawi Z, Helbig I
  
• Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of Hyperphosphatasia with Mental Retardation Syndrome. Hum Mutat. 2016 Aug;37(8):737-44
  Knaus A, Awaya T, Helbig I, Afawi Z, Pendziwiat M, …, Krawitz PM
  
• Seizures as presenting and prominent symptom in chorea-acanthocytosis with c.2343del VPS13A gene mutation. Epilepsia. 2016 Apr;57(4):549-56
  Benninger F, Afawi Z, Korczyn AD, …, Helbig I, Berkovic SF, Blatt I
  
• Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies. Brain. 2017 Sep 1;140(9):2337-2354
  Masnada S, Hedrich UBS, …, Helbig I, …, Rubboli G
  
• Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes. JAMA Neurol. 2017 Oct 1;74(10):1228-1236
  de Kovel CGF, Syrbe S, …, Afawi Z, Klein KM, …, Pendziwiat M, Helbig I, …, Koeleman BPC
  
• The phenotypic spectrum of ARHGEF9 includes intellectual disability, focal epilepsy and febrile seizures. J Neurol. 2017 Jul;264(7):1421-1425
  Klein KM, Pendziwiat M, …, Kanaan M, Helbig I, Afawi Z; Israeli-Palestinian Epilepsy Family Consortium
  
• Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood. Am J Hum Genet. 2018 Apr 5;102(4):557-573
  Vögtle FN, Brändl B, Larson A, Pendziwiat M, …, Helbig I
  
• A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy. Am J Hum Genet. 2019 May 2. pii: S0002-9297(19)30147-8
  Helbig I, Lopez-Hernandez T, …, Weber YG; EuroEPINOMICS-RES Consortium; GRIN Consortium
  
• Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish. Nat Commun. 2019 Feb 12;10(1):708
  Siekierska A, Stamberger H, …, Helbig I; C4RCD Research Group; AR working group of the EuroEPINOMICS RES Consortium, Weckhuysen S, Francklyn C, Antonellis A, de Witte P, De Jonghe P
  
• Inclusion of hemimegalencephaly into the phenotypic spectrum of NPRL3 pathogenic variants in familial focal epilepsy with variable foci. Epilepsia. 2019 May 21
  Canavati C, Klein KM, Afawi Z, Pendziwiat M, Abu Rayyan, A, Kamal, L, Zahdeh, F, Qaysia, I, Helbig I, Kanaan, M