Location: Cleveland Clinic Main Campus
The Lal Research Group focuses on the discovery, evaluation, and translation of biomarker into clinical care. Specifically, we aim to develop computational methods which integrate large genetic, clinical, and biological data sets to improve the prediction of patient outcomes – paving the way for personalized medicine.
Dennis is Assistant Professor in the Department of Molecular Medicine in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (CCLCM) and Assistant Staff in the Genomic Medicine Institute with a secondary staff appointment in the Neurological Institute’s Epilepsy Center both Cleveland, US. In addition to his primary appointments in Cleveland, he is Visiting Scientist at the Broad Institute of Harvard and M.I.T., Cambridge, US as well as Group Leader at the Cologne Center for Genomics, Cologne, Germany.
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
View publications for Dennis Lal, PhD
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The Lal Rsearch Group commits to depositing all manuscripts from our lab on an open access preprint server (such as bioRxiv.org) no later than the time of submission, in order to ensure rapid evaluation and use of the findings by the broadest possible community.
Required: Doctorate in computational biology, biology, computer science, electrical engineering, statistics, or physics, obtained within the last five years. Submitted first-author or joint first-author papers in any of the project relevant fields. Experience of working in a Linux environment. Demonstrated proficiency in at least two of the following programming languages Python, Perl, Java, Matlab, R, bash, and C++.
Not required, but preferred qualifications: First-author papers published in peer-reviewed journals or a preprint archive. Demonstrated research interaction with medical doctors or biologist. Basic training in genetics.
Dr. Lal and colleagues have developed a statistical model that integrates genetic and clinical data to calculate the probability of developing Dravet syndrome.
Dr. Lal’s team will perform the most comprehensive genetic analysis of focal cortical dysplasia (FCD) to confirm proposed FCD-associated genes and identify novel FCD causal genes and variants.
These awards provide Drs. Eng, Lal and Lesmana with seed funding for their highly innovative and potentially impactful cancer research projects.
Dr. Lal’s team conducted the first big data characterization of missense variants from 1,300 disease-associated genes to identify features associated with pathogenic and benign variants.
Dr. Lal adjusted and used a statistical model based on mutation rate to predict the annual number of new cases of over 100 rare monogenetic neurodevelopmental disorders caused by de novo variants, offering previously unavailable estimates for disease burden.