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About me

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.

Research description

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:


Team members:



  • Miriam Armenio, Research Assistant
  • Alisa Foerster, Master student
  • Amel Al-Murrani, Research Assistant

Academic honours, awards and prizes

Academic honors, awards and prizes:

2015 Recipient of of the Jeanssons Foundation personal award to particularly outstanding young researchers

2015-2017 Recipient of a three-year fellowship from Riksbankens Jubileumsfond

2015-2018 Awarded four years of funding from Svenska Sällskapet för Medicinsk Forskning (SSMF:s stora anslag)

2015-2017 Awarded 3 years of funding for clinical scientists from Marianne och Marcus Wallenbergs Stiftelse

2016-2019 Selected for four year funding as Research Associate (forskarassistent), Karolinska Institutet


AMYCNE: Confident copy number assessment using whole genome sequencing data
Eisfeldt J, Nilsson D, Andersson-assarsson Jc, Lindstrand A
PloS one 2018;13(3):e0189710-

Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP
Adnp Consortium, Van Dijck A, Vulto-van Silfhout At, Cappuyns E, Van Der Werf Im, Mancini Gm, et al
Biological psychiatry 2018;():-

De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy
Kiselev A, Vaz R, Knyazeva A, Khudiakov A, Tarnovskaya S, Liu J, et al
Human mutation 2018;():-

High-resolution detection of chromosomal rearrangements in leukemias through mate pair whole genome sequencing
Tran An, Taylan F, Zachariadis V, Ivanov Öfverholm I, Lindstrand A, Vezzi F, et al
PloS one 2018;13(3):e0193928-

Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes
Grochowski Cm, Gu S, Yuan B, Tcw J, Brennand Kj, Sebat J, et al
Human mutation 2018;39(7):939-946

Rare Copy Number Variants in Array-Based Comparative Genomic Hybridization in Early-Onset Skeletal Fragility
Costantini A, Skarp S, Kampe A, Makitie Re, Pettersson M, Mannikko M, et al

Targeted copy number screening highlights an intragenic deletion of WDR63 as the likely cause of human occipital encephalocele and abnormal CNS development in zebrafish
Hofmeister W, Pettersson M, Kurtoglu D, Armenio M, Eisfeldt J, Papadogiannakis N, et al
Human mutation 2018;39(4):495-505

A Large Inversion Involving GNAS Exon A/B and All Exons Encoding Gsα Is Associated With Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B)
Grigelioniene G, Nevalainen Pi, Reyes M, Thiele S, Tafaj O, Molinaro A, et al
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2017;32(4):776-783

Copy Number Variants Are Enriched in Individuals With Early-Onset Obesity and Highlight Novel Pathogenic Pathways
Pettersson M, Viljakainen H, Loid P, Mustila T, Pekkinen M, Armenio M, et al
The Journal of clinical endocrinology and metabolism 2017;102(8):3029-3039

Further evidence for specific IFIH1 mutation as a cause of Singleton-Merten syndrome with phenotypic heterogeneity
Pettersson M, Bergendal B, Norderyd J, Nilsson D, Anderlid Bm, Nordgren A, et al
American journal of medical genetics. Part A 2017;173(5):1396-1399

Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains
Geisheker Mr, Heymann G, Wang T, Coe Bp, Turner Tn, Stessman Haf, et al
Nature neuroscience 2017;20(8):1043-1051

Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism
Bramswig Nc, Lüdecke Hj, Pettersson M, Albrecht B, Bernier Ra, Cremer K, et al
Human genetics 2017;136(2):179-192

Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies
Hammarsjö A, Wang Z, Vaz R, Taylan F, Sedghi M, Girisha Km, et al
Scientific reports 2017;7(1):15585-

PLS3 Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization
Kämpe Aj, Costantini A, Levy-shraga Y, Zeitlin L, Roschger P, Taylan F, et al
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
Stessman Haf, Xiong B, Coe Bp, Wang Ty, Hoekzema K, Fenckova M, et al
NATURE GENETICS 2017;49(4):515-526

TIDDIT, an efficient and comprehensive structural variant caller for massive parallel sequencing data
Eisfeldt J, Vezzi F, Olason P, Nilsson D, Lindstrand A
F1000Research 2017;6():664-

Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights the Importance of Microhomology in the Mechanism of Formation
Nilsson D, Pettersson M, Gustavsson P, Förster A, Hofmeister W, Wincent J, et al
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
Tham E, Eklund Ea, Hammarsjö A, Bengtson P, Geiberger S, Lagerstedt-robinson K, et al
European journal of human genetics : EJHG 2016;24(2):198-207

Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome
Lindstrand A, Frangakis S, Carvalho Cm, Richardson Eb, Mcfadden Ka, Willer Jr, et al
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
Molecular Basis Of Periodontal Eds Consortium, Kapferer-seebacher I, Pepin M, Werner R, Aitman Tj, Nordgren A, et al
American journal of human genetics 2016;99(5):1005-1014

Autosomal recessive mutations in the COL2A1 gene cause severe spondyloepiphyseal dysplasia
Tham E, Nishimura G, Geiberger S, Horemuzova E, Nilsson D, Lindstrand A, et al
Clinical genetics 2015;87(5):496-8

CTNND2-a candidate gene for reading problems and mild intellectual disability
Hofmeister W, Nilsson D, Topa A, Anderlid Bm, Darki F, Matsson H, et al
Journal of medical genetics 2015;52(2):111-22

Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features
Tham E, Lindstrand A, Santani A, Malmgren H, Nesbitt A, Dubbs Ha, et al
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
Viljakainen H, Andersson-assarsson Jc, Armenio M, Pekkinen M, Pettersson M, Valta H, et al
PloS one 2015;10(7):e0131883-

WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish
Baranowska Körberg I, Hofmeister W, Markljung E, Cao J, Nilsson D, Ludwig M, et al
Human molecular genetics 2015;24(18):5069-78

Different mutations in PDE4D associated with developmental disorders with mirror phenotypes
Lindstrand A, Grigelioniene G, Nilsson D, Pettersson M, Hofmeister W, Anderlid Bm, et al
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
Laurell T, Nilsson D, Hofmeister W, Lindstrand A, Ahituv N, Vandermeer J, et al
Molecular genetics & genomic medicine 2014;2(5):402-11

Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome
Lindstrand A, Davis Ee, Carvalho Cm, Pehlivan D, Willer Jr, Tsai Ic, et al
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
Kvarnung M, Nilsson D, Lindstrand A, Korenke Gc, Chiang Sc, Blennow E, et al
Journal of medical genetics 2013;50(8):521-8

ARMC4 Mutations Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry
Hjeij R, Lindstrand A, Francis R, Zariwala Ma, Liu Xq, Li Y, et al

Exome Capture Reveals ZNF423 and CEP164 Mutations, Linking Renal Ciliopathies to DNA Damage Response Signaling
Chaki M, Airik R, Ghosh Ak, Giles Rh, Chen R, Slaats Gg, et al
CELL 2012;150(3):533-48

Inherited mosaicism for the supernumerary marker chromosome in cat eye syndrome: inter- and intra-individual variation and correlation to the phenotype
Kvarnung M, Lindstrand A, Malmgren H, Thåström A, Jacobson L, Dahl N, et al
American journal of medical genetics. Part A 2012;158A(5):1111-7

Detailed molecular and clinical characterization of three patients with 21q deletions
Lindstrand A, Malmgren H, Sahlen S, Schoumans J, Nordgren A, Ergander U, et al
CLINICAL GENETICS 2010;77(2):145-54

Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes
Bruno Dl, Anderlid Bm, Lindstrand A, Van Ravenswaaij-arts C, Ganesamoorthy D, Lundin J, et al

Improved structural characterization of chromosomal breakpoints using high resolution custom array-CGH
Lindstrand A, Schoumans J, Gustavsson P, Hanemaaijer N, Malmgren H, Blennow E
CLINICAL GENETICS 2010;77(6):552-62

Molecular and Clinical Characterization of Patients With Overlapping 10p Deletions
Lindstrand A, Malmgren H, Verri A, Benetti E, Eriksson M, Nordgren A, et al

Molecular Cytogenetic Characterization of a Constitutional, Highly Complex Intrachromosomal Rearrangement of Chromosome 1, With 14 Breakpoints and a 0.5 Mb Submicroscopic Deletion
Lindstrand A, Malmgren H, Sahlen S, Xin H, Schoumans J, Blennow E

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