Goldstein Lab

Location and Contact Information

701 West 168th Street, 6-601
New York, NY 10032
United States

Research in the Goldstein Lab covers a broad range of human genetics, from the identification of new disease-causing genes to the development of new treatment options that are targeted to the underlying causes of disease. Along with large networks of collaborators, the Goldstein Lab has been responsible for a number of well-known discoveries, including the gene responsible for alternating hemiplegia of childhood and the role of the IL28B gene in treatment response to hepatitis C infection.

As director of the Sequencing, Biostatistics, and Bioinformatics Core for the Epi4K Consortium, Dr. Goldstein led the collaboration that discovered three novel epilepsy genes. His group has also been involved in some of the early applications of next generation sequencing in the study of undiagnosed diseases and has discovered a number of new syndromes through the careful evaluation of individual patient genomes, including NGLY1 deficiency and, more recently, the neurodevelopmental disease caused by mutation in GNB1.

In addition to gene discovery, the Goldstein Lab is also involved in the development of methods to aid the interpretation of genome sequence data, including the first approach that used population genetic data to identify genes and genomic regions most likely to carry mutations that cause disease. This intolerance-scoring framework is now being refined not only to help discriminate benign and pathogenic mutations in genes but also to identify pathogenic mutations in non-coding parts of the genome.

The Goldstein Lab is dedicated to the functional characterization of mutations that cause disease and the development of in vitro modeling paradigms that are amenable to medium and high throughput screens to facilitate the identification of new treatment options for defined genetic conditions. A major focus in this regard is the genetic epilepsies, where we are using cultured neuronal networks monitored with multi-electrode arrays (MEAs) to define clear, in vitro phenotypes for epilepsy mutations. Once such phenotypes are defined, we will screen both available drugs and indicated compounds to find candidate treatments based on the in vitro effects. The leading candidates will then be assessed in the appropriate mouse models and eventually in patients with the relevant genetic epilepsy.

Current Projects

  • Identifying regulatory mutations that influence neuropsychiatric disease
  • ALS Genome Sequencing Consortium with Biogen Idec
  • An integrated and diverse genomic medicine program for undiagnosed diseases
  • Epilepsy Genetics Initiative
  • Epilepsy Genetics and disease mutation modeling
  • Epi4K Center without walls: Sequencing, Biostatistics and Bioinformatics Core
  • Epi4K: Gene Discovery in 4,000 Epilepsy Genomes
  • EpiMiRNA: MicroRNAs in the Pathogenesis, Treatment and Prevention of Epilepsy
  • Identification of Rare Variants of OCD
  • Identifying de novo mutations causing OCD in trios by whole exome sequencing
  • Healthcare provider organization site for the national Precision Medicine Initiative Cohort Program

Lab Members

  • Anna Alkelai, PhD

    • Associate Research Scientist

    Anna Alkelai, PhD, is an experienced experimental geneticist and bioinformatics analyst with industry and academic experience. Anna received her Bachelor of Science in life sciences, a Master of Science in medical genetics and doctoral degree in neurobiology and genetics. Her scientific training and research in molecular genetics focused on implementation of various molecular and computational methods to search for mutations causing severe neurological or neuropsychiatric conditions. Anna’s current role is to lead a large-scale collaborative sequencing project of hundreds of patients presenting with schizophrenia and other neuropsychiatric disorders.

  • Evan Baugh, PhD

    • Postdoctoral Research Scientist

    Evan works on developing computational methods for predicting and interpreting the effects of missense mutations associated with human diseases to improve diagnosis for variants of uncertain significance. To better understand the functional and structural effects of missense mutations, these methods integrate diverse resources, including intra- and interspecies conservation, sub-genic functional annotations, and energetics derived from Monte Carlo-based structural analysis
    (Rosetta) using machine learning. Evan is passionate about understanding proteins and their mutations, obtaining a BS in chemical engineering from Johns Hopkins University, focused on heteropolymers and protein engineering, and a PhD in bioinformatics from New York University where he applied machine learning methods to automate the interpretation of missense mutation structural effects (VIPUR). Recently, Evan has focused on combining sub-genic protein annotations to provide a functional profile for every position in the human exome to improve the diagnosis of missense mutations, the interpretation of similarity to known pathogenic variants, and the identification of phenotype-specific trends within and across genes.

  • Sophie Colombo, PhD

    • Associate Research Scientist

    Sophie obtained her BSc in biology and MSc in genetics from Denis Diderot University in Paris, France. She then earned a PhD in genetics and developmental biology from the Institute Curie and Denis Diderot University in Paris, France. Sophie moved to New York to pursue research in developmental biology as a postdoctoral research scientist at Columbia University. She joined the Institute for Genomic Medicine in 2015 to focus on translational research that may directly impact patients' health. She is currently working on two rare and severe genetic neurodevelopmental disorders, KCNT1 nocturnal frontal lobe epilepsy, and GNB1 syndrome, trying to understand the underlying pathological mechanisms of disease and identify potential therapeutics.

  • Ryan Dhindsa

    • Graduate Student

    Ryan Dhindsa is an MD/PhD student in the Goldstein Lab. He received his bachelor’s degree in biology with a concentration in genomics from Duke University in 2011. He is interested in using single-cell RNA-sequencing and machine learning to identify drug repositioning opportunities for severe neurodevelopmental diseases.

  • Sarah Dugger

    • Graduate Student

    Sarah is a PhD student in the Goldstein Lab. She previously obtained her undergraduate degree in biology and a master’s degree in genetic counseling from Case Western Reserve University in Cleveland, Ohio. Prior to returning to graduate school, Sarah was a practicing full-time prenatal genetic counselor in Dayton, Ohio—an experience that sparked her interest in translational medicine. As a graduate student, she is now working to understand the pathogenic mechanisms underlying a severe neurodevelopmental syndrome caused by mutations in the gene HNRNPU.

  • Daniel K. Krizay

    • Graduate Student

    Daniel Krizay is a student in the Department of Genetics and Development. He obtained a BS in biochemistry from Northeastern University, as well as an MA and MPhil in genetics and developmental biology from Columbia University. Before attending Columbia University, Daniel worked for two years as a research associate at Cubist Pharmaceuticals and Pfizer in the Departments of Microbiology and Rare Diseases, respectively. He is currently working on many projects in the Goldstein Lab, ranging from neurodevelopmental transcriptomics to the experimental deconvolution of neuronal subtype connectivity.

  • Irina Lebedeva, PhD

    • Associate Research Scientist
  • Joshua Motelow

    • Postdoctoral Research Scientist
  • Tess Pottinger

    • Postdoctoral Research Scientist
  • Neha S. Raghavan, PhD

    • Postdoctoral Research Scientist
  • Andrew Ressler

    • Graduate Student

    Andrew Ressler graduated from Brown University in 2013 with a Bachelor’s of Science in applied math-biology. He then worked at Amgen for two years as a finance associate before joining the systems biology PhD program in the summer of 2015. As a PhD candidate in the Goldstein and Boland Labs, Andrew is developing novel differentiation paradigms to study neurodevelopmental disorders in cultured human neural networks.

  • Patrick Shea, PhD

    • Associate Research Scientist

    Patrick received his PhD in human genetics from the University of Pittsburgh. Following a two-year fellowship in bacterial disease genomics, he completed his postdoctoral research with the Goldstein Lab at the Duke University Center for Human Genome Variation. His research is focused on understanding how human genetic variation contributes to differences in susceptibility to liver and infectious diseases.

  • Xinchen Wang, PhD

    • Postdoctoral Research Scientist

    Xinchen Wang joined the Goldstein lab as a postdoc at the end of 2017. He is interested in using computational and experimental approaches to study how genetic variation in the non-coding genome contributes to human disease, with a focus on neurological diseases. Originally from Toronto, Canada, Xinchen obtained his BSc in biochemistry at the University of Toronto, and his PhD in biology from the Massachusetts Institute of Technology where he studied the genetic regulation of gene expression.

  • Damian Willams

    • Associate Research Scientist

    Damian has been studying neuronal function using electrophysiology and imaging techniques throughout his research career. For his doctorate in Tom Cunnane’s laboratory in the Department of Pharmacology at the University of Oxford, Damian studied neurotransmission in sympathetic neurons. Damian’s used calcium imaging and electrophysiology to study neurotransmitter release at individual nerve terminal varicosities and nicotinic receptor-mediated modulation of sympathetic neurotransmitter release.

    After his DPhil, Damian joined Stephen Ikeda’s lab at NIAAA in Bethesda, Maryland. During this postdoctoral training, Damian studied the mechanisms involved in voltage-gated calcium channel modulation. Damian also developed a method for high-efficiency heterologous proteins expression in adult primary neurons, and a method for rapid modification of proteins in live cells using an inducible protease system.

    Damian continued his postdoctoral training in Amy MacDermott’s laboratory studying the physiological properties of stem cell-derived neurons. During this time and his position of managing the electrophysiology and Calcium Imaging Section of the Columbia Stem Cell Core, Damian has gained extensive experience of stem cell-derived tissues. He has been central to projects which span across the field, including the characterization of stem cell lines, understanding the mechanisms of neuronal development and disease, and the development of drug screening platforms for ALS and neuromuscular disease.

    Research Overview

    The aim of Damian’s research is to understand functional changes in neurons that occur in epilepsy and intellectual disability. Using a variety of electrophysiological and image-based techniques, Damian can identify changes at molecular, individual neuron, and synaptic levels. This work is carried out with the Boland, Goldstein and Frankel laboratories, using murine and stem cell-based models that harbor disease-causing genetic variants identified at the IGM. Insight into the mechanism of changes to neuron function will provide novel drug targets to specific biological processes, which has the potential to improve treatment of previously intractable disease.

Former Trainees

  • Ayal Gussow, PhD (2013-2016)

    • Thesis: Non-protein-coding variants in the context of disease
  • Sarah Kleinstein (2012-2017)

    • Thesis: Human genomics of complex trait severity
  • Melodi McSweeney, PhD (2013-2017)

    • Thesis: Microelectrode array modeling of genetic neurological disorders in the era of next generation sequencing
  • Xiaolin Zhu, PhD (2012-2017)

    • Thesis: Human genetics of HIV-1 infection based on next-generation sequencing analysis
  • Yi-Fan Lu, PhD (2010-2015)

    • Thesis: Mechanistic study of IL28B association with hepatitis C treatment and clearance
  • Elizabeth Ruzzo, PhD (2009-2014)

    • Thesis: Identification of pathogenic variants in a cohort of epilepsy families
  • Kimberly Pelak, PhD (2008-2012)

    • Thesis: Human Genetics; HIV host genetics
  • Elizabeth Cirulli, PhD (2006-2010)

    • Thesis: Genetics of ALS/aging/HIV resistance
  • Nicole Walley, MS (2006-2009)

    • Thesis: Pharmacogenetics of Epilepsy / Genetics of HIV in African Americans
  • Gianpiero Cavallieri, PhD (2001-2005)

    • Thesis: Haplotype Mapping in Epilepsy genetics and pharmacogenetics
  • Sarah K. Tate, PhD (2001-2005)

    • Thesis: Clinical applications of pharmacogenetics
  • Julia Abernethy, PhD (2000-2004)

    • Thesis: Recent Human History: Inferences from the Y-Chromosome and Mitrochondrial DNA
  • James Wilson, PhD (1998-2003)

    • Thesis: Human population structure and demographic history using genetic markers
  • Neil Bradman, PhD (1997-2000)

    • Thesis: The use of Y chromosome haplotypes to study relationships within and among populations in Africa and the Near East with particular reference to Jewish communities and sub-groups
  • Stuart Macdonald, PhD (1997-2000)

    • Thesis: Evolutionary and genomic analysis of complex traits of Drosphila
  • Isabelle Colson, PhD (1997-2000)

    • Thesis: The genetics of adaptation and reproductive isolation in the Drosophila Melanogaster Species Complex
  • David E. Reich, PhD (1997-2000)

    • Thesis: Statistical analysis of human evolutionary history with implications for gene mapping

Select Publications

  • Hayeck TJ, Stong N, Wolock CJ, Copeland B, Kamalakaran S, Goldstein DB, Allen AS. Improved pathogenic variant localization via a hierarchical model of sub-regional intolerance. Am J Hum Genet. 2019 Jan 18. [Epub ahead of print]

  • Groopman EE, Marasa M, Cameron-Christie S, Petrovski S, Aggarwal VS, Milo-Rasouly H, Li Y, Zhang J, Nestor J, Krithivasan P, Lam WY, Mitrotti A, Piva S, Kil BH, Chatterjee D, Reingold R, Bradbury D, DiVecchia M, Snyder H, Mu X, Mehl K, Balderes O, Fasel DA, Weng C, Radhakrishnan J, Canetta P, Appel GB, Bomback AS, Ahn W, Uy NS, Alam S, Cohen DJ, Crew RJ, Dube GK, Rao MK, Kamalakaran S, Copeland B, Ren Z, Bridgers J, Malone CD, Mebane CM, Dagaonkar N, Fellstrom BC, Haefliger C, Mohan S, Sanna-Cherchi S, Kiryluk K, Fleckner J, March R, Platt A, Goldstein DB, Gharavi AG. Diagnostic utility of exome sequencing for kidney disease.N Engl J Med. 2019 Jan 10;380(2):142-151.

  • International League Against Epilepsy Consortium on Complex Epilepsies. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun. 2018 Dec 10;9(1):5269.

  • Gelfman S, Wang Q, Lu YF, Hall D, Bostick CD, Dhindsa R, Halvorsen M, McSweeney KM, Cotterill E, Edinburgh T, Beaumont MA, Frankel WN, Petrovski S, Allen AS, Boland MJ, Goldstein DB, Eglen SJ. meaRtools: An R package for the analysis of neuronal networks recorded on microelectrode arrays. PLoS Comput Biol. 2018 Oct 1;14(10):e1006506.

  • Kleinstein SE, Rein M, Abdelmalek MF, Guy CD, Goldstein DB, Mae Diehl A, Moylan CA.Whole-Exome Sequencing Study of Extreme Phenotypes of NAFLD. Hepatol Commun. 2018 Sep 5;2(9):1021-1029.

  • Hemati P, Revah-Politi A, Bassan H, Petrovski S, Bilancia CG, Ramsey K, Griffin NG, Bier L, Cho MT, Rosello M, Lynch SA, Colombo S, Weber A, Haug M, Heinzen EL, Sands TT, Narayanan V, Primiano M, Aggarwal VS, Millan F, Sattler-Holtrop SG, Caro-Llopis A, Pillar N, Baker J, Freedman R, Kroes HY, Sacharow S, Stong N, Lapunzina P, Schneider MC, Mendelsohn NJ, Singleton A, Loik Ramey V, Wou K, Kuzminsky A, Monfort S, Weiss M, Doyle S, Iglesias A, Martinez F, Mckenzie F, Orellana C, van Gassen KLI, Palomares M, Bazak L, Lee A, Bircher A, Basel-Vanagaite L, Hafstrom M, Houge G; C4RCD Research Group; DDD study, Goldstein DB, Anyane-Yeboa K. Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature. Am J Med Genet A. 2018 Nov;176(11):2259-2275.

  • Mulhern MS, Stumpel C, Stong N, Brunner HG, Bier L, Lippa N, Riviello J, Rouhl RPW, Kempers M, Pfundt R, Stegmann APA, Kukolich MK, Telegrafi A, Lehman A; CAUSES study, Lopez-Rangel E, Houcinat N, Barth M, den Hollander N, Hoffer MJV, Weckhuysen S; EuroEPINOMICS-RES-MAE working group, Roovers J, Djemie T, Barca D, Ceulemans B, Craiu D, Lemke JR, Korff C, Mefford HC, Meyers CT, Siegler Z, Hiatt SM, Cooper GM, Bebin EM, Snijders Blok L, Veenstra-Knol HE, Baugh EH, Brilstra EH, Volker-Touw CML, van Binsbergen E, Revah-Politi A, Pereira E, McBrian D, Pacault M, Isidor B, Le Caignec C, Gilbert-Dussardier B, Bilan F, Heinzen EL, Goldstein DB, Stevens SJC, Sands TT. NBEA: Developmental disease gene with early generalized epilepsy phenotypes. Ann Neurol. 2018 Nov;84(5):788-795.

  • Wattacheril J, Shea PR, Mohammad S, Behling C, Aggarwal V, Wilson LA, Yates KP, Ito J, Fishbein M, Stong N, Lavine JE, Goldstein DB. Exome sequencing of an adolescent with nonalcoholic fatty liver disease identifies a clinically actionable case of Wilson disease. Cold Spring Harb Mol Case Stud. 2018 Oct 1;4(5). pii: a003087.

  • Raghavan NS, Brickman AM, Andrews H, Manly JJ, Schupf N, Lantigua R, Wolock CJ, Kamalakaran S, Petrovski S, Tosto G, Vardarajan BN, Goldstein DB, Mayeux R; Alzheimer's Disease Sequencing Project. Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Ann Clin Transl Neurol. 2018 May 24;5(7):832-842.

  • Shashi V, Schoch K, Spillmann R, Cope H, Tan QK, Walley N, Pena L, McConkie-Rosell A, Jiang YH, Stong N, Need AC, Goldstein DB; Undiagnosed Diseases Network. A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative. Genet Med. 2019 Jan;21(1):161-172.

  • Kleinstein SE, Shea PR, Allen AS, Koelle DM, Wald A, Goldstein DB. Genome-wide association study (GWAS) of human host factors influencing viral severity of herpes simplex virus type 2 (HSV-2). Genes Immun. 2018 Feb 28. doi: 10.1038/s41435-018-0013-4. [Epub ahead of print]

  • Kleinstein SE, Shea PR, Stamm LM, Sulkowski M, Goldstein DB, Naggie S. Association of CYP2B6 Single-Nucleotide Polymorphisms Altering Efavirenz Metabolism With Hepatitis C Virus (HCV) Treatment Relapse Among Human Immunodeficiency Virus/HCV-Coinfected African Americans Receiving Ledipasvir/Sofosbuvir in the ION-4 Trial. Clin Infect Dis. 2018 Jun 1;66(12):1953-1956.

  • Gussow AB, Copeland BR, Dhindsa RS, Wang Q, Petrovski S, Majoros WH, Allen AS, Goldstein DB. Orion: Detecting regions of the human non-coding genome that are intolerant to variation using population genetics. PLoS One. 2017 Aug 10;12(8):e0181604. Erratum in: PLoS One. 2018 Jan 11;13(1):e0191298.

  • Gussow AB, Copeland BR, Dhindsa RS, Wang Q, Petrovski S, Majoros WH, Allen AS, Goldstein DB. Orion: Detecting regions of the human non-coding genome that are intolerant to variation using population genetics. PLoS One. 2017 Aug 10;12(8):e0181604. Erratum in: PLoS One. 2018 Jan 11;13(1):e0191298.

  • Zhu X, Padmanabhan R, Copeland B, Bridgers J, Ren Z, Kamalakaran S, O'Driscoll-Collins A, Berkovic SF, Scheffer IE, Poduri A, Mei D, Guerrini R, Lowenstein DH, Allen AS, Heinzen EL, Goldstein DB. A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations. PLoS Genet. 2017 Nov 29;13(11):e1007104.

  • Revah-Politi A, Ganapathi M, Bier L, Cho MT, Goldstein DB, Hemati P, Iglesias A, Juusola J, Pappas J, Petrovski S, Wilson AL, Aggarwal VS, Anyane-Yeboa K. Loss-of-function variants in NFIA provide further support that NFIA is a critical gene in 1p32-p31 deletion syndrome: A four patient series. Am J Med Genet A. 2017 Dec;173(12):3158-3164.

  • Gelfman S, Wang Q, McSweeney KM, Ren Z, La Carpia F, Halvorsen M, Schoch K, Ratzon F, Heinzen EL, Boland MJ, Petrovski S, Goldstein DB. Annotating pathogenic non-coding variants in genic regions. Nat Commun. 2017 Aug 9;8(1):236.

  • Petrovski S, Todd JL, Durheim MT, Wang Q, Chien JW, Kelly FL, Frankel C, Mebane CM, Ren Z, Bridgers J, Urban TJ, Malone CD, Finlen Copeland A, Brinkley C, Allen AS, O'Riordan T, McHutchison JG, Palmer SM, Goldstein DB. An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis. Am J Respir Crit Care Med. 2017 Jul 1;196(1):82-93

  • McSweeney KM, Gussow AB, Bradrick SS, Dugger SA, Gelfman S, Wang Q, Petrovski S, Frankel WN, Boland MJ, Goldstein DB. Inhibition of microRNA 128 promotes excitability of cultured cortical neuronal networks.Genome Res. 2016 Oct;26(10):1411-1416. Epub 2016 Aug 11.

  • Petrovski S, Goldstein DB. Unequal representation of genetic variation across ancestry groups creates healthcare inequality in the application of precision medicine. Genome Biol. 2016 Jul 14;17(1):157.