Research

Spatial multi-omics

A human body comprises approximately 100 trillion cells. As most of our organ functions are executed by the concerted action of those individual cells in a spatially organised context, it is paramount to research these individual cells in their native spatial context. This is not only important to understand normal organ development and function, but also to investigate how cells are perturbed in diseased conditions. Technological developments in the last few years allow us to assay the expression of hundreds to thousands of genes at single-cell resolution while retaining the complete morphological and spatial information.

At LMIB, we are at the fore-front of the development of these technologies by working together with technologists and biologists, as part of the Leuven Single-Cell Institute, to create the next generation of spatial multi-omic technologies. We aim to develop novel data fusion strategies which integrate information gained from conventional microscopy with sub-cellular resolution multi-omics information by leveraging state-of-the-art deep neural network architectures.

Variant Prioritization

Genome sequencing studies reveal thousands to millions of genetic variants in any typical individual. These genetic variants are often benign, but a small subset can give rise to disease. However, the fundamental challenge of distinguishing between neutral and pathogenic variants is often non-trivial, and follow-up investigation of variants is often time and cost-prohibitive. Therefore, variant prioritization tools are needed which rank the most likely candidates based on available information on the nature of the respective variants, the genes wherein they reside, the tissues wherein these genes are expressed and the patient’s phenotypic presentation.

At LMIB we aim to develop variant prioritization tools leveraging the latest publicly available data and state-of-the-art machine learning algorithms and apply these tools in large-scale genetic studies in order to further understand the genetic etiology of human diseases and to provide improved genetic diagnostic outputs for patients.

Highlighted

A multi-omics genome-and-transcriptome single-cell atlas of human preimplantation embryogenesis reveals the cellular and molecular impact of chromosome instability

Elia Fernandez Gallardo, Alejandro Sifrim, Joel Chappell, Jonas Demeulemeester, Jennifer Clara Herrmann, ..., Joris Robert Vermeesch, Karen Peeraer, Sophie Debrock, Vincent Pasque, Thierry Voet

Cold Spring Harbor Laboratory   ·   10 Mar 2023   ·   doi:10.1101/2023.03.08.530586

All

2023

Assessing the contribution of rare variants to congenital heart disease through a large-scale case-control exome study

Enrique Audain, Anna Wilsdon, Gregor Dombrowsky, Alejandro Sifrim, Jeroen Breckpot, ..., Hans-Heiner Kramer, Vivek Iyer, Lars Allan Larsen, J David Brook, Marc-Phillip Hitz

Cold Spring Harbor Laboratory   ·   28 Dec 2023   ·   doi:10.1101/2023.12.23.23300495

A multi-omics genome-and-transcriptome single-cell atlas of human preimplantation embryogenesis reveals the cellular and molecular impact of chromosome instability

Elia Fernandez Gallardo, Alejandro Sifrim, Joel Chappell, Jonas Demeulemeester, Jennifer Clara Herrmann, ..., Joris Robert Vermeesch, Karen Peeraer, Sophie Debrock, Vincent Pasque, Thierry Voet

Cold Spring Harbor Laboratory   ·   10 Mar 2023   ·   doi:10.1101/2023.03.08.530586

2021

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Enrique Audain, Anna Wilsdon, Jeroen Breckpot, Jose M. G. Izarzugaza, Tomas W. Fitzgerald, ..., Gregor Andelfinger, Matthew E. Hurles, Bernard Thienpont, Lars Allan Larsen, Marc-Phillip Hitz

PLOS Genetics   ·   29 Jul 2021   ·   doi:10.1371/journal.pgen.1009679

2020

Detecting cryptic clinically-relevant structural variation in exome sequencing data increases diagnostic yield for developmental disorders

Eugene J. Gardner, Alejandro Sifrim, Sarah J. Lindsay, Elena Prigmore, Diana Rajan, ..., Hilary C. Martin, Caroline F. Wright, David R. FitzPatrick, Helen V. Firth, Matthew E. Hurles

Cold Spring Harbor Laboratory   ·   02 Oct 2020   ·   doi:10.1101/2020.10.02.20194241

Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease

Jose M. G. Izarzugaza, Sabrina G. Ellesøe, Canan Doganli, Natasja Spring Ehlers, Marlene D. Dalgaard, ..., Sabine Klaassen, J. David Brook, Marc-Phillip Hitz, Lars A. Larsen, Søren Brunak

Genome Medicine   ·   28 Aug 2020   ·   doi:10.1186/s13073-020-00772-z

Heterotypic cell–cell communication regulates glandular stem cell multipotency

Alessia Centonze, Shuheng Lin, Elisavet Tika, Alejandro Sifrim, Marco Fioramonti, ..., Viviane de Maertelaer, Christian W. Siebel, Alexandra Van Keymeulen, Thierry Voet, Cédric Blanpain

Nature   ·   26 Aug 2020   ·   doi:10.1038/s41586-020-2632-y

Mechanisms of stretch-mediated skin expansion at single-cell resolution

Mariaceleste Aragona, Alejandro Sifrim, Milan Malfait, Yura Song, Jens Van Herck, ..., Seungmin Han, Fadel Tissir, Thierry Voet, Benjamin D. Simons, Cédric Blanpain

Nature   ·   29 Jul 2020   ·   doi:10.1038/s41586-020-2555-7

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

E Audain, A Wilsdon, J Breckpot, JMG Izarzugaza, TW Fitzgerald, ..., G Andelfinger, ME Hurles, B Thienpont, LA Larsen, MP Hitz

Cold Spring Harbor Laboratory   ·   25 Jun 2020   ·   doi:10.1101/2020.06.25.169573

Interstitial Cell Remodeling Promotes Aberrant Adipogenesis in Dystrophic Muscles

Jordi Camps, Natacha Breuls, Alejandro Sifrim, Nefele Giarratana, Marlies Corvelyn, ..., Rik Gijsbers, Giulio Cossu, Yvan Torrente, Thierry Voet, Maurilio Sampaolesi

Cell Reports   ·   01 May 2020   ·   doi:10.1016/j.celrep.2020.107597

Defining the Design Principles of Skin Epidermis Postnatal Growth

Sophie Dekoninck, Edouard Hannezo, Alejandro Sifrim, Yekaterina A. Miroshnikova, Mariaceleste Aragona, ..., Christine Dubois, Thierry Voet, Sara A. Wickström, Benjamin D. Simons, Cédric Blanpain

Cell   ·   01 Apr 2020   ·   doi:10.1016/j.cell.2020.03.015

The contribution of X-linked coding variation to severe developmental disorders

Hilary C. Martin, Eugene J. Gardner, Kaitlin E. Samocha, Joanna Kaplanis, Nadia Akawi, ..., Jeremy McRae, Caroline F. Wright, David R. FitzPatrick, Helen V. Firth, Matthew E. Hurles

Cold Spring Harbor Laboratory   ·   23 Mar 2020   ·   doi:10.1101/2020.03.18.20037960

2019

Systems genetics analysis identify calcium signalling defects as novel cause of congenital heart disease

Jose M.G. Izarzugaza, Sabrina G. Ellesøe, Canan Doganli, Natasja Spring Ehlers, Marlene D. Dalgaard, ..., Marc Gewillig, J. David Brook, Marc-Phillip Hitz, Lars A. Larsen, Søren Brunak

Cold Spring Harbor Laboratory   ·   12 Dec 2019   ·   doi:10.1101/2019.12.11.872424

Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data

Stuart Aitken, Helen V. Firth, Jeremy McRae, Mihail Halachev, Usha Kini, ..., H.V. Firth, D.R. FitzPatrick, C.F. Wright, J.C. Barrett, M.E. Hurles

The American Journal of Human Genetics   ·   01 Nov 2019   ·   doi:10.1016/j.ajhg.2019.09.015

Contribution of retrotransposition to developmental disorders

Eugene J. Gardner, Elena Prigmore, Giuseppe Gallone, Petr Danecek, Kaitlin E. Samocha, ..., Katrina Prescott, Elisabeth Rosser, David R. FitzPatrick, Helen V. Firth, Matthew E. Hurles

Nature Communications   ·   11 Oct 2019   ·   doi:10.1038/s41467-019-12520-y

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, ..., Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles

The American Journal of Human Genetics   ·   01 Jun 2019   ·   doi:10.1016/j.ajhg.2019.03.021

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, ..., John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu

The American Journal of Human Genetics   ·   01 May 2019   ·   doi:10.1016/j.ajhg.2019.03.005

HiVA: an integrative wet- and dry-lab platform for haplotype and copy number analysis of single-cell genomes

Masoud Zamani Esteki, Amin Ardeshirdavani, Daniel Alcaide, Heleen Masset, Jia Ding, ..., Eftychia Dimitriadou, Jan Aerts, Thierry Voet, Yves Moreau, Joris Robert Vermeesch

Cold Spring Harbor Laboratory   ·   07 Mar 2019   ·   doi:10.1101/564914

2018

Contribution of Retrotransposition to Developmental Disorders

Eugene J. Gardner, Elena Prigmore, Giuseppe Gallone, Petr Danecek, Kaitlin E. Samocha, ..., Katrina Prescott, Elisabeth Rosser, David R. FitzPatrick, Helen V. Firth, Matthew E. Hurles

Cold Spring Harbor Laboratory   ·   16 Nov 2018   ·   doi:10.1101/471375

CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Lot Snijders Blok, Justine Rousseau, Joanna Twist, Sophie Ehresmann, Motoki Takaku, ..., Tjitske Kleefstra, Han G. Brunner, Paul A. Wade, Simon E. Fisher, Philippe M. Campeau

Nature Communications   ·   05 Nov 2018   ·   doi:10.1038/s41467-018-06014-6

Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders

Caroline F. Wright, Jeremy F. McRae, Stephen Clayton, Giuseppe Gallone, Stuart Aitken, ..., Michael J. Parker, Jeffrey C. Barrett, Matthew E. Hurles, David R. FitzPatrick, Helen V. Firth

Genetics in Medicine   ·   01 Oct 2018   ·   doi:10.1038/gim.2017.246

Early lineage segregation of multipotent embryonic mammary gland progenitors

Aline Wuidart, Alejandro Sifrim, Marco Fioramonti, Shigeru Matsumura, Audrey Brisebarre, ..., Anne Dannau, Christine Dubois, Alexandra Van Keymeulen, Thierry Voet, Cédric Blanpain

Nature Cell Biology   ·   21 May 2018   ·   doi:10.1038/s41556-018-0095-2

Identification of the tumour transition states occurring during EMT

Ievgenia Pastushenko, Audrey Brisebarre, Alejandro Sifrim, Marco Fioramonti, Tatiana Revenco, ..., Isabelle Salmon, Jean-Christophe Marine, Thierry Voet, Panagiota A. Sotiropoulou, Cédric Blanpain

Nature   ·   01 Apr 2018   ·   doi:10.1038/s41586-018-0040-3

De novo mutations in regulatory elements in neurodevelopmental disorders

Patrick J. Short, Jeremy F. McRae, Giuseppe Gallone, Alejandro Sifrim, Hyejung Won, ..., Caroline F. Wright, Helen V. Firth, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles

Nature   ·   01 Mar 2018   ·   doi:10.1038/nature25983

Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders

Víctor Faundes, William G. Newman, Laura Bernardini, Natalie Canham, Jill Clayton-Smith, ..., Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. . Hurles

The American Journal of Human Genetics   ·   01 Jan 2018   ·   doi:10.1016/j.ajhg.2017.11.013

2017

Not all SCN1A epileptic encephalopathies are Dravet syndrome

Lynette G. Sadleir, Emily I. Mountier, Deepak Gill, Suzanne Davis, Charuta Joshi, ..., Wayne Lam, Wendy D. Jones, Yanick Crow, Zara Skitt, Zosia Miedzybrodzka

Neurology   ·   05 Sep 2017   ·   doi:10.1212/wnl.0000000000004331

Detection of structural mosaicism from targeted and whole-genome sequencing data

Daniel A. King, Alejandro Sifrim, Tomas W. Fitzgerald, Raheleh Rahbari, Emma Hobson, ..., Sarju G. Mehta, Mohammed Shehla, Susan E. Tomkins, Pradeep C. Vasudevan, Matthew E. Hurles

Genome Research   ·   30 Aug 2017   ·   doi:10.1101/gr.212373.116

Clinical and molecular consequences of disease-associated de novo mutations in SATB2

Hemant Bengani, Mark Handley, Mohsan Alvi, Rita Ibitoye, Melissa Lees, ..., Helen V. Firth, F. Lucy Raymond, Usha Kini, Christoffer Nellåker, David R. FitzPatrick

Genetics in Medicine   ·   01 Aug 2017   ·   doi:10.1038/gim.2016.211

Recent advances in congenital heart disease genomics

Anna Wilsdon, Alejandro Sifrim, Marc-Phillip Hitz, Matthew Hurles, J. David Brook

F1000Research   ·   12 Jun 2017   ·   doi:10.12688/f1000research.10113.1

De novo mutations in regulatory elements cause neurodevelopmental disorders

Patrick J. Short, Jeremy F. McRae, Giuseppe Gallone, Alejandro Sifrim, Hyejung Won, ..., Caroline F. Wright, Helen V. Firth, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles

Cold Spring Harbor Laboratory   ·   13 Mar 2017   ·   doi:10.1101/112896

Prevalence and architecture of de novo mutations in developmental disorders

[no author info]

Nature   ·   25 Jan 2017   ·   doi:10.1038/nature21062

2016

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Alejandro Sifrim, Marc-Phillip Hitz, Anna Wilsdon, Jeroen Breckpot, Saeed H Al Turki, ..., Jeffrey C Barrett, Koenraad Devriendt, David R FitzPatrick, J David Brook, Matthew E Hurles

Nature Genetics   ·   01 Aug 2016   ·   doi:10.1038/ng.3627

Comparison of aggregation methods for multiphenotype exomic variant prioritization

Alejandro Sifrim, Dusan Popovic, Joris R. Vermeesch, Jan Aerts, Bart De Moor, Yves Moreau

Cold Spring Harbor Laboratory   ·   20 Jul 2016   ·   doi:10.1101/064899

Detection of structural mosaicism from targeted and whole-genome sequencing data

Daniel A. King, Alejandro Sifrim, Tomas W. Fitzgerald, Raheleh Rahbari, Emma Hobson, ..., Sarju G. Mehta, Mohammed Shehla, Susan E. Tomkins, Pradeep C. Vasudevan, Matthew E. Hurles

Cold Spring Harbor Laboratory   ·   07 Jul 2016   ·   doi:10.1101/062620

Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation: The Deciphering Developmental Disorders Study

Jeremy F McRae, Stephen Clayton, Tomas W Fitzgerald, Joanna Kaplanis, Elena Prigmore, ..., Helen V Firth, Caroline F Wright, David R FitzPatrick, Jeffrey C Barrett, Matthew E Hurles

Cold Spring Harbor Laboratory   ·   20 Apr 2016   ·   doi:10.1101/049056

2015

Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type

Mala Isrie, Martin Breuss, Guoling Tian, Andi Harley Hansen, Francesca Cristofoli, ..., Joris Robert Vermeesch, Erica E. Davis, Nicholas J. Cowan, David Anthony Keays, Hilde Van Esch

The American Journal of Human Genetics   ·   01 Dec 2015   ·   doi:10.1016/j.ajhg.2015.10.014

A Note on the Evaluation of Mutation Prioritization Algorithms

Dusan Popovic, Jesse Davis, Alejandro Sifrim, Bart De Moor

2015 IEEE Symposium Series on Computational Intelligence   ·   01 Dec 2015   ·   doi:10.1109/ssci.2015.193

Mutations in NONO lead to syndromic intellectual disability and inhibitory synaptic defects

Dennis Mircsof, Maéva Langouët, Marlène Rio, Sébastien Moutton, Karine Siquier-Pernet, ..., Arnold Munnich, Jeanne Amiel, Steven A Brown, Shiva K Tyagarajan, Laurence Colleaux

Nature Neuroscience   ·   16 Nov 2015   ·   doi:10.1038/nn.4169

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

Nadia Akawi, Jeremy McRae, Morad Ansari, Meena Balasubramanian, Moira Blyth, ..., Helen V Firth, Jeffrey C Barrett, Cecilia W Lo, David R FitzPatrick, Matthew E Hurles

Nature Genetics   ·   05 Oct 2015   ·   doi:10.1038/ng.3410

Beegle:from literature mining to disease-gene discovery

Sarah ElShal, Léon-Charles Tranchevent, Alejandro Sifrim, Amin Ardeshirdavani, Jesse Davis, Yves Moreau

Nucleic Acids Research   ·   17 Sep 2015   ·   doi:10.1093/nar/gkv905

Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data

Caroline F Wright, Tomas W Fitzgerald, Wendy D Jones, Stephen Clayton, Jeremy F McRae, ..., Nigel P Carter, Jeffrey C Barrett, Matthew E Hurles, David R FitzPatrick, Helen V Firth

The Lancet   ·   01 Apr 2015   ·   doi:10.1016/s0140-6736(14)61705-0

Problems with the nested granularity of feature domains in bioinformatics: the eXtasy case

Dusan Popovic, Alejandro Sifrim, Jesse Davis, Yves Moreau, Bart De Moor

BMC Bioinformatics   ·   23 Feb 2015   ·   doi:10.1186/1471-2105-16-s4-s2

2014

Large-scale discovery of novel genetic causes of developmental disorders

[no author info]

Nature   ·   24 Dec 2014   ·   doi:10.1038/nature14135

Synaptic, transcriptional and chromatin genes disrupted in autism

Silvia De Rubeis, Xin He, Arthur P. Goldberg, Christopher S. Poultney, Kaitlin Samocha, ..., David J. Cutler, Kathryn Roeder, Bernie Devlin, Mark J. Daly, Joseph D. Buxbaum

Nature   ·   29 Oct 2014   ·   doi:10.1038/nature13772

A Self-Tuning Genetic Algorithm with Applications in Biomarker Discovery

Dusan Popovic, Charalampos Moschopoulos, Ryo Sakai, Alejandro Sifrim, Jan Aerts, Yves Moreau, Bart De Moor

2014 IEEE 27th International Symposium on Computer-Based Medical Systems   ·   01 May 2014   ·   doi:10.1109/cbms.2014.10

2013

eXtasy simplified-towards opening the black box

Dusan Popovic, Alejandro Sifrim, Yves Moreau, Bart De Moor

2013 IEEE International Conference on Bioinformatics and Biomedicine   ·   01 Dec 2013   ·   doi:10.1109/bibm.2013.6732713

eXtasy: variant prioritization by genomic data fusion

Alejandro Sifrim, Dusan Popovic, Leon-Charles Tranchevent, Amin Ardeshirdavani, Ryo Sakai, Peter Konings, Joris R Vermeesch, Jan Aerts, Bart De Moor, Yves Moreau

Nature Methods   ·   29 Sep 2013   ·   doi:10.1038/nmeth.2656

Unraveling genomic variation from next generation sequencing data

Georgios A Pavlopoulos, Anastasis Oulas, Ernesto Iacucci, Alejandro Sifrim, Yves Moreau, Reinhard Schneider, Jan Aerts, Ioannis Iliopoulos

BioData Mining   ·   25 Jul 2013   ·   doi:10.1186/1756-0381-6-13

TrioVis: a visualization approach for filtering genomic variants of parent–child trios

Ryo Sakai, Alejandro Sifrim, Andrew Vande Moere, Jan Aerts

Bioinformatics   ·   08 May 2013   ·   doi:10.1093/bioinformatics/btt267

Meander: visually exploring the structural variome using space-filling curves

G. A. Pavlopoulos, P. Kumar, A. Sifrim, R. Sakai, M. L. Lin, T. Voet, Y. Moreau, J. Aerts

Nucleic Acids Research   ·   19 Apr 2013   ·   doi:10.1093/nar/gkt254

A Hybrid Approach to Feature Ranking for Microarray Data Classification

Dusan Popovic, Alejandro Sifrim, Charalampos Moschopoulos, Yves Moreau, Bart De Moor

Engineering Applications of Neural Networks   ·   01 Jan 2013   ·   doi:10.1007/978-3-642-41016-1_26

A Genetic Algorithm for Pancreatic Cancer Diagnosis

Charalampos Moschopoulos, Dusan Popovic, Alejandro Sifrim, Grigorios Beligiannis, Bart De Moor, Yves Moreau

Engineering Applications of Neural Networks   ·   01 Jan 2013   ·   doi:10.1007/978-3-642-41016-1_24

2012

Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome

Jeroen K J Van Houdt, Beata Anna Nowakowska, Sérgio B Sousa, Barbera D C van Schaik, Eve Seuntjens, ..., Orsetta Zuffardi, Antoine H C van Kampen, Koenraad Devriendt, Raoul Hennekam, Joris Robert Vermeesch

Nature Genetics   ·   26 Feb 2012   ·   doi:10.1038/ng.1105

Annotate-it: a Swiss-knife approach to annotation, analysis and interpretation of single nucleotide variation in human disease

Alejandro Sifrim, Jeroen KJ Van Houdt, Leon-Charles Tranchevent, Beata Nowakowska, Ryo Sakai, Georgios A Pavlopoulos, Koen Devriendt, Joris R Vermeesch, Yves Moreau, Jan Aerts

Genome Medicine   ·   01 Jan 2012   ·   doi:10.1186/gm374

A Simple Genetic Algorithm for Biomarker Mining

Dusan Popovic, Alejandro Sifrim, Georgios A. Pavlopoulos, Yves Moreau, Bart De Moor

Pattern Recognition in Bioinformatics   ·   01 Jan 2012   ·   doi:10.1007/978-3-642-34123-6_20

2011

Medusa: A tool for exploring and clustering biological networks

Georgios A Pavlopoulos, Sean D Hooper, Alejandro Sifrim, Reinhard Schneider, Jan Aerts

BMC Research Notes   ·   06 Oct 2011   ·   doi:10.1186/1756-0500-4-384

2010

Alternative Experimental Design with an Applied Normalization Scheme Can Improve Statistical Power in 2D-DIGE Experiments

Kristof Engelen, Alejandro Sifrim, Babs Van de Plas, Kris Laukens, Lutgarde Arckens, Kathleen Marchal

Journal of Proteome Research   ·   24 Aug 2010   ·   doi:10.1021/pr100010u