I am Associate Professor and Consultant in Clinical Genetics in Stockholm, Sweden. Currently I am the head of the Clinical Genetics diagnostic laboratory (Karolinska University Hospital) and group leader for Rare Diseases research group at the Department of Molecular Medicine and Surgery (Karolinska Institutet). I presented my thesis in January 2010 and after that completed a postdoc at Duke University North Carolina USA. My specific area of interest is the study of structural human genomic variation, its biological consequences and involvement in rare and common human disorders.
My group members combine conventional and next generation genetic analysis with careful clinical assessments and functional follow up in vivo (zebrafish) and in vitro (primary cells). To characterize the breakpoints of chromosome rearrangements we use a variety of methodologies and next generation sequencing (NGS) platforms.
This work is truly translational! Patients are initially identified in the health care system and outlined phenotypically and cytogenetically in the clinical genetic service. Then the research part takes over aiming to outline the exact genetic rearrangement down to single gene and breakpoint level in order to correlate symptoms with a specific gene defect. Finally, our findings are returned to the health care system in the form of new information about gene function.
Project 1: The role of structural genomic variation in human health and disease
Backgound: Structural genomic variation comprises 1) copy-neutral balanced events (inversions and translocations) as well as 2) unbalanced events with either loss or gain of chromosome material (deletions, duplications, triplications and multi allelic copy number variants (CNVs). The size may vary from events that are visible in a light microscope (>5-10 Mb) down to the size of a single exon (<100-200 base pairs). In the past decade structural variants have emerged as important contributors to the genetic load of both rare and common disorders especially within the area of neurodevelopmental disease and malformation syndromes. However, a specific rearrangement often affects many genes and regulatory regions and the specific disease causing factors are still poorly characterized.
Aim: These studies are focused on the detailed characterization of structural genomic rearrangements in order to identify the specific causative and modifying genes and to understand the underlying mutational mechanisms involved.
Work Plan: We use whole genome sequencing (WGS) to characterize and identify structural variants. Patents with structural variants are recruited through the clinical genetic diagnostic laboratory where individuals with neurodevelopmental disorders and malformation syndromes are analyzed with chromosome analysis and/or oligonucleotide array-based comparative genomic hybridization (aCGH). We have also developed a custom designed high-resolution aCGH platform. This array platform provides exon resolution in 2000 target genes important for ciliary function and embryo development. After WGS and bioinformatics analysis functional follow up studies of candidate genes and variants are done in primary patient cells (e.g. fibroblasts, lymphocytes), induced pluripotent stem cells and in zebrafish.
We have several ongoing studies:
Study I) Identification and characterization of rare disease associated structural chromosomal variants by massive parallel whole genome sequencing
The first objective is to implement WGS for the clinical diagnostic detection of structural variants. To this end, we develop novel bioinformatic analysis pipelines to identify both balanced and unbalanced structural variants from WGS data. The second objective is to study the rearrangement breakpoints and from the mutational signatures observed, infer the underlying mechanisms involved. Finally, we are interested in how the genes affected by structural variants cause disease. Our ambition is to characterize all genetic lesions in a given patient, from single base pair changes to large chromosomal rearrangements, and to follow up with functional studies. In this way, we will evaluate the relationship between structural variants and the burden of point mutations (an area that is still largely unexplored).
Study II) Identification of new disease genes by sequencing balanced chromosomal aberrations.
In this project we use WGS (described above) to study balanced chromosomal rearrangements (inversions and translocations). The hypothesis is that genes disrupted by the chromosomal breakpoints are driving the clinical symptoms seen in the rearrangement carriers. Identified candidate genes are evaluated in zebrafish.
III) Rare and common structural chromosomal variants in children with early onset obesity
This project, done in collaboration with Professor Outimaija Mäkitie, focus on the involvement of structural variation in children with early onset obesity. We know that genetic factors are important for the development of both mild and severe forms of obesity but the majority of the underlying genetics is still unknown. Especially in children with early-onset obesity we suspected a genetic defect. We have shown previously that the copy number variable region affecting the AMY1 gene is associated with early onset female obesity. We are now extending these studies into other genomic regions. Studies are done using targeted aCGH and WGS.
IV) Structural chromosomal variants in children with malformation syndromes
In this project, done in collaboration with Professor Agneta Nordenskjöld, we study point mutations and copy number variants in patients with congenital malformations by targeted aCGH and WGS.
V) Genetics of gonadal dysgenesis and primary ovarian insufficiency
In this project, done in collaboration with Ameli Norling and Professor Angelica Hirschberg, we study point mutations and copy number variants in patients with gonadal dysgenesis or primary ovarian insufficiency by targeted aCGH and WGS and relate this information to inheritance and disease causing probability.
Project 2: Zebrafish models and genetic mechanisms underlying rare human disorders
Despite recent progress in identifying the genetic cause of rare disorders we still lack the ability to interpret the pathogenic potential of rare variants identified in small families or in uncharacterized genes and assess the genetic basis of variability in clinical presentations. Due to the technical advantages, the zebrafish has become a very popular model to test and further understand the role of candidate genes in disease. Approximately 70% of the human genes have a zebrafish orthologue and many of the cellular pathways in embryonic development and tissue function are similar to those found in humans. One of the most commonly used techniques to assess the role of a specific gene is to knockdown the target protein levels using antisense oligonucleotides or morpholinos. This technique is however being replaced by the use of the genome editing technique CRISPR/Cas9. The CRISPR/Cas9 technique results in permanent changes in the genome that, given the specificity of the technique, more closely resemble the mutations found in the patients.
In this project we evaluate novel genes and mutations identified in patients with rare diseases investigated with clinical exome/whole genome sequencing or through our research studies outlined above. We use overexpression of wild type and mutated RNA, transient knock down (morpholinos) and stable knockdown (CRISPR/Cas9 mutagenesis). Disorders of particular interest are ciliopathies, gonadal dysgenesis, congenital malformation syndromes and muscle disorders.
Previous and Current Research Funding:
- 2017-2019 Stockholms läns landsting, HMT
- 2017-2019 Stockholms läns landsting, ALF
- 2015-2018 Svenska Sällskapet för Medicinsk Forskning
- 2015-2017 Marianne och Marcus Wallenbergs Stiftelse
- 2015-2016 Science for Life Laboratory
- 2015-2017 Riksbankens Jubileumsfond
- 2015-2016 Jeanssons Foundation
- 2014-2016 Hjärnfonden
- 2015-2016 Kungl. Fysiografiska Sällskapet i Lund
- 2013-2015 Swedish Research Council (Vetenskapsrådet)
- 2016-2019 Karolinska Institutet
- 2013-2015 Stockholms läns landsting, ALF
- 2010-2013 Swedish Research Council (Vetenskapsrådet)
- Anna Lindstrand, MD, PhD, Team Leader
- Wolfgang Hofmeister, PhD, Assistant professor
- Ameli Norling, MD, PhD, Postdoc
- Josephine Wincent, MD, PhD, Postdoc
- Raquel Vaz, PhD, Postdoc
- Maria Pettersson, PhD student
- Jesper Eisfeldt, PhD student
- Miriam Armenio, Research Assistant
- Alisa Foerster, Master student
- Amel Al-Murrani, Research Assistant
Academic honours, awards and prizes
Academic honors, awards and prizes:
2016-2019 Selected for four year funding as Research Associate (forskarassistent), Karolinska Institutet
Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains
Nature neuroscience 2017;20(8):1043-1051
Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies
Scientific reports 2017;7(1):15585-
PLS3 Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2017;32(12):2394-2404
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases
NATURE GENETICS 2017;49(4):515-526
TIDDIT, an efficient and comprehensive structural variant caller for massive parallel sequencing data
Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights the Importance of Microhomology in the Mechanism of Formation
Human mutation 2017;38(2):180-192
A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9
European journal of human genetics : EJHG 2016;24(2):198-207
Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome
American journal of human genetics 2016;99(2):318-36
Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement
American journal of human genetics 2016;99(5):1005-1014
Autosomal recessive mutations in the COL2A1 gene cause severe spondyloepiphyseal dysplasia
Clinical genetics 2015;87(5):496-8
CTNND2-a candidate gene for reading problems and mild intellectual disability
Journal of medical genetics 2015;52(2):111-22
Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features
American journal of human genetics 2015;96(3):507-13
Low Copy Number of the AMY1 Locus Is Associated with Early-Onset Female Obesity in Finland
PloS one 2015;10(7):e0131883-
WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish
Human molecular genetics 2015;24(18):5069-78
Different mutations in PDE4D associated with developmental disorders with mirror phenotypes
Journal of medical genetics 2014;51(1):45-54
Identification of three novel FGF16 mutations in X-linked recessive fusion of the fourth and fifth metacarpals and possible correlation with heart disease
Molecular genetics & genomic medicine 2014;2(5):402-11
Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome
American journal of human genetics 2014;94(5):745-54
A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT
Journal of medical genetics 2013;50(8):521-8
ARMC4 Mutations Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry
AMERICAN JOURNAL OF HUMAN GENETICS 2013;93(2):357-67
Inherited mosaicism for the supernumerary marker chromosome in cat eye syndrome: inter- and intra-individual variation and correlation to the phenotype
American journal of medical genetics. Part A 2012;158A(5):1111-7
Detailed molecular and clinical characterization of three patients with 21q deletions
CLINICAL GENETICS 2010;77(2):145-54
Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes
JOURNAL OF MEDICAL GENETICS 2010;47(5):299-311
Improved structural characterization of chromosomal breakpoints using high resolution custom array-CGH
CLINICAL GENETICS 2010;77(6):552-62
Molecular and Clinical Characterization of Patients With Overlapping 10p Deletions
AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2010;152A(5):1233-43
Molecular Cytogenetic Characterization of a Constitutional, Highly Complex Intrachromosomal Rearrangement of Chromosome 1, With 14 Breakpoints and a 0.5 Mb Submicroscopic Deletion
AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2008;146A(24):3217-22