Research

Current research projects include:

• Gene and risk loci discovery using genetic data from in-house and globally collected epilepsy patient cohorts.
• Developing novel methods for missense variant interpretation.
• Characterization of patient disease trajectories using electronic health records as well characterizing patient brain tissues by analysing single cell RNA sequencing, brain neurophysiology and imaging data sets.

Previous and ongoing research:

Epilepsy Disease Gene Discovery

In recent years, we conducted multiple epilepsy gene discovery studies using whole exome sequencing data of patients with epilepsy syndromes. The investigated phenotype in these studies ranged from Rolandic Epilepsy (RE)- the most common epilepsy syndrome in childhood to severe rare forms of epileptic encephalopathies.

a) Lemke JR*, Lal D*, Reinthaler EM, Steiner I, et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013 Sep;45(9):1067-72. doi: 10.1038/ng.2728. PMID: 23933819.

b) Lal D, Reinthaler EM, Schubert J, et al. DEPDC5 mutations in genetic focal epilepsies of childhood. Ann Neurol. 2014 May;75(5):788-92. doi: 10.1002/ana.24127. PMID: 24591017.

c) Reinthaler EM*, Dejanovic B*, Lal D*, et al. Rare variants in γ-aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes. Ann Neurol. 2015 Jun;77(6):972-86. doi: 10.1002/ana.24395 PMID: 25726841

d) Heyne H, EuroEPINOMICS RES Consortium, Jamra RA, … , Sisodiya SM, Helbig I, Lal D, Lemke JR. The Spectrum Of De Novo Variants In Neurodevelopmental Disorders With Epilepsy. Nature Genetics 2018 (provisionally accepted)

Epilepsy Copy Number Risk Allele Discovery

Copy number variants (CNVs) confer risk or cause neurodevelopmental disorders. The degree to which CNVs contribute to epilepsy was not clear.

a) Dejanovic B*, Lal D*, Catarino CB, et al. Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy. Neurobiol Dis. 2014 Jul;67:88-96. doi: 10.1016/j.nbd.2014.02.001. PMID: 24561070.

b) Reinthaler EM*, Lal D*, Lebon S, et al. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy. Hum Mol Genet. 2014 Nov 15;23(22):6069-80. doi: 10.1093/hmg/ddu306. PMID: 24939913.

c) Lal D, Ruppert AK, Trucks H, et al. Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. PLoS Genet. 2015 May 7;11(5):e1005226. doi: 10.1371/journal.pgen.1005226. PMID: 25950944

d) Pérez-Palma E, Helbig I, Klein KM, … , Perucca E, Zara F, Weber YG, Lal D. Heterogeneous Contribution of Microdeletions in the Development of Common Generalized and Focal epilepsies J Med Genet. 2017 Jul 29. pii: jmedgenet-2016-104495. doi: 10.1136/jmedgenet-2016-104495. PubMed PMID: 28756411

Genetics of Neurodevelopmental Disorders

In addition to large-scale epilepsy genetics studies we also directed multiple smaller scale and family studies to identify underlying genetic pathologies in patients with neurodevelopmental disorders.

a) Lal D, Becker K, Motameny S, et al. Homozygous missense mutation of NDUFV1 as the cause of infantile bilateral striatal necrosis. Neurogenetics. 2013 Feb;14(1):85-7. doi: 10.1007/s10048-013-0355-z. PMID: 23334465.

b) Lal D, Neubauer BA, Toliat MR, et al. Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing. PLoS One. 2016 Jan 20;11(1):e0146040. doi: 10.1371/journal.pone.0146040 PMID: 26789268

c) Hardies K, de Kovel CG, Weckhuysen S, … , Lal D, et al. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia. Brain. 2015 Nov;138(Pt 11):3238-50. doi: 10.1093/brain/awv263. PMID: 26384929.

d) Pérez-Palma E, Saarentaus E, Andrieux J, … , Isidor B, Neubauer BA, Lal D. Heterogeneous duplications at 19q13.33 in patients with neurodevelopmental disorders with and without seizures. Neurology Genetics (in press)

Interpretation and Translation of genetic variants

The introduction of clinical gene sequencing has exponentially facilitated the discovery of variants in known disease associated genes in patients as wells as in healthy individuals. However, not all variants are pathogenic. Our long-term research interests involve the development of a comprehensive understanding of how alterations in the genome contribute to brain disorders.

a) Lemke JR, Geider K, Helbig KL, … , Lal D, et al. Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy. Neurology. 2016 Jun 7;86(23):2171-8. doi: 10.1212/WNL.0000000000002740. PMID: 27164704; PubMed Central PMCID: PMC4898312.

b) Lal D, Reinthaler EM, Dejanovic B, et al. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes. PLoS One. 2016 Mar 18;11(3):e0150426. doi: 10.1371/journal.pone.0150426. PubMed PMID: 26990884

c) Neupert LM, Nothnagel M, May P, Palotie A, Daly M, Nürnberg P, Blümcke I, Lal D. Reassessment Of Lesion-Associated Gene And Variant Pathogenicity In Focal Human Epilepsies. BioRxiv 2017; doi: https://doi.org/10.1101/130203

d) Lal D, May P, Samocha K, et al. Gene family information facilitates variant interpretation and identification of disease-associated genes. BioRxiv 2017; doi: https://doi.org/10.1101/159780