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Karolinska universitetssjukhuset

A. Lindstrand and A. Nordgren Group

Rare Diseases


There are approximately 8000 different rare diseases, affecting 6% or about 350 million people in the world. The quality of life of patients and families with rare diseases is often compromised by the lack of a correct molecular diagnosis, leading to risk of wrong diagnosis and inaccurate treatments. To ensure access to appropriate treatments and quality personalized health care, more information about the whole life perspective of the disease is needed.

Research Projects – Rare Diseases

The rare diseases group study rare diseases both clinically and at the molecular level to improve genetic diagnostics, increase knowledge about genotype-phenotype correlations and understand disease biology. The long-term goal is to identify biomarkers and to develop personalized therapeutics in order to improve the quality of life for individuals with rare diseases.

The group conducts translational research studies and we focus our efforts in the following major areas:

New gene discoveries and identification of novel mutational mechanisms

In close collaboration with the multidisciplinary team and clinical exome/WGS program in the clinical genetic diagnostic laboratory we follow up on new candidate disease genes in patients, cells, and zebrafish. Rare diseases can affect any organ but we have a special interest in the following disorders:

  • Intellectual disability and autism
  • Isolated brain malformations and malformation syndromes
  • Ciliopathies
  • Skeletal dysplasias
  • Neuromuscular disorders

By studying patients and families with these rare diseases we will not only discover new disease genes but also identify novel mutational mechanisms. Through multidisciplinary collaboration we will gain insight in fundamental disease generating pathways that may be transferred to common diseases such as neuropsychiatric disorders, sporadic malformations and cancer.

Cancer predisposition syndromes and familial childhood cancers

Our research is directed at identifying human disease genes that predispose to childhood cancer. In order to discover cancer predisposition genes and increase our understanding of cancer causation we use different approaches such as registry-based studies, molecular studies of rare families with familial clustering of childhood cancers, patients with rare syndromes or overgrowth who developed cancer and isolated cases who developed cancer in childhood. We perform a careful clinical and dysmorphological evaluation and we compare germline variants with parental DNA and somatically mutated cancer genes in order increase our understanding about to how germline mutations confer increased risks of childhood cancer.

The role of structural genomic variation in human health and disease

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. Our 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. We use whole genome sequencing (WGS) to characterize and identify structural variants. Patients 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.

Functional evaluation of genetic findings in zebrafish and cells

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. First we evaluate effects on expression and splicing patient cell lines using RT-PCR, qPCR and Western blotting. Then functional studies are performed in two principle model systems:

Induced pluripotent stem cells (iPS cells): To study underlying disease mechanism at the cellular level in affected tissue we generate iPS cells through the re-programing of fibroblasts using the KI stem cell core. Then, in collaboration with Anna Falk, the iPS cells are induced into neuronal stem cells enabling directly study the effects of early neurogenesis in cells from patients compared with cells derived from normal controls.

Zebrafish: 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. To model mutations identified in patents we use overexpression of wild type and mutated RNA, transient knock down (morpholinos) and stable knockdown (CRISPR/Cas9 mutagenesis).

Psychological and ethnological studies of patients and families living with rare diseases

People with rare syndromes have in common that some problems may still be unknown due to the fact that the diagnosis is rare. For the most part, hardly anyone in the area knows anything about the diagnosis. It is therefore not enough to struggle with the consequences of the diagnosis. You must also fight against ignorance to claim the right to support from health care and society.

Individuals with rare syndromes have unique needs and problems that are caused by the syndrome. For example, different behaviors are more common in individuals with specific diagnoses, such as severe mood swings with Smith-Magenis syndrome, increased appetite with Prader-Willis syndrome, severe anxiety and anxiety disorder with Williams syndrome and risk of depression and other mental illness in 22q11 deletion carriers. The underlying cause of these psychological symptoms that occur in different syndromes is poorly investigated, which means that you cannot offer individuals with rare syndromes an optimal treatment. The main objective of the project is to increase the information about living with a particular diagnosis in order to better customize the diagnosis, treatment and care for the patient and his/her family.

Group Leaders

Anna Lindstrand, adjunct professor, anna.lindstrand@ki.se

Ann Nordgren, adjunct professor, ann.nordgren@ki.se

Group members

See list of members of the A. Lindstrand and A. Nordengren Group on the Karolinska Institutet webpage.

Undiagnosed disease program (UDP)

In order to improve diagnostics of patients with unknown often ultra-rare disorders researcher and clinical experts collaborate in the Karolinska Undiagnosed Diseases Program diagnostic team (K-UDP).

K-UDP is a novel national initiative where Karolinska will be the coordinating center and SciLifeLab the sequencing core. This national initiative will facilitate new gene discoveries and studies of mechanisms in undiagnosed diseases. The Rare Diseases research group is also a member of the Undiagnosed Diseases Network International (UDNI) – an international collaboration with other clinical and research sites worldwide among them several top universities from the USA. The UDP concept requires international collaboration and multidisciplinary one-stop shop outpatient clinics for diagnostics of patients with rare diseases of all ages.

In August 2017 the 5th international conference on rare and undiagnosed diseases was placed in Stockholm.

Selected publications Anna Lindstrand

Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders Batkovskyte D, Mckenzie F, Taylan F, Simsek-kiper Po, Nikkel Sm, Ohashi H, Stevenson Re, Ha T, Cavalcanti Dp, Miyahara H, Skinner Sa, Aguirre Ma, Akçören Z, Utine Ge, Chiu T, Shimizu K, Hammarsjö A, Boduroglu K, Moore Hw, Louie Rj, Arts P, Merrihew An, Babic M, Jackson Mr, Papadogiannakis N, Lindstrand A, Nordgren A, Barnett Cp, Scott Hs, Chagin As, Nishimura G, Grigelioniene G. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2023;38(5):692-706

A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies Aranda-guillén M, Røyrvik Ec, Fletcher-sandersjöö S, Artaza H, Botusan Ir, Grytaas Ma, Hallgren Å, Breivik L, Pettersson M, Jørgensen Ap, Lindstrand A, Vogt E, Husebye Es, Kämpe O, Wolff Asb, Bensing S, Johansson S, Eriksson D, Norwegian Addison Registry Study Group The Swedish Addison Registry Study Group. Journal of internal medicine 2023;294(1):96-109

Case report: Extending the spectrum of clinical and molecular findings in FOXC1 haploinsufficiency syndrome. Flores Ag, Nordgren I, Pettersson M, Dias-santagata D, Nilsson D, Hammarsjo A, Lindstrand A, Batkovskyte D, Wiggs J, Walton Ds, Goldenberg P, Eisfeldt J, Lin Ae, Lachman Rs, Nishimura G, Grigelioniene G. Frontiers in Genetics 2023;:1174046-

Expanding the phenotype of Seckel syndrome associated with biallelic loss-of-function variants in CEP63. Pacheco Np, Pettersson M, Lindstrand A, Grigelioniene G. Americal Journal of Medical Genetics Part A. 2023;191(7):1929-1934

Genome sequencing with comprehensive variant calling identifies structural variants and repeat expansions in a large fraction of individuals with ataxia and/or neuromuscular disorders. Ek M, Nilsson D, Engvall M, Malmgren H, Thonberg H, Pettersson M, Anderlid Bm, Hammarsjo A, Helgadottir Ht, Arnardottir S, Naess K, Nennesmo I, Paucar M, Hjartarson Ht, Press R, Solders G, Sejersen T, Lindstrand A, Kvarnung M. Frontiers in Neurology 2023;:1170005-

Loss of ctnnd2b affects neuronal differentiation and behavior in zebrafish. Vaz R, Edwards S, Duenas-rey A, Hofmeister W, Lindstrand A. Frontiers in Neuroscience 2023;:1205653-

Precision medicine and rare diseases in pediatric urology. Nordgren A, Lindstrand A, Wu Hy, Fossum M. Journal of pediatric urology 2023;19(3):335-338

Reduced cone photoreceptor function and subtle systemic manifestations in two siblings with loss of SCLT1. Pechhacker Mkg, Molnar A, Pacheco Np, Thonberg H, Querat L, Birkeldh U, Nordgren A, Lindstrand A. Ophthalmic Genetics 2023;:1-8

The cost-effectiveness of whole genome sequencing in neurodevelopmental disorders. Runheim H, Pettersson M, Hammarsjö A, Nordgren A, Henriksson M, Lindstrand A, Levin LÅ, Soller Mj. Scientific reports 2023;13(1):6904-

Transposable element insertions in 1000 Swedish individuals. Bilgrav Saether K, Nilsson D, Thonberg H, Tham E, Ameur A, Eisfeldt J, Lindstrand A. PloS one 2023;18(7):e0289346-

Selected publications Ann Nordgren

A full PubMed list of Ann Nordgren’s publications is found here. 

About CMM

The Center for Molecular Medicine (CMM) is a foundation instituted by the Stockholm County Council (Region Stockholm). CMM is at the heart of a close partnership with the Karolinska University Hospital and Karolinska Institutet, fueling advancements in biomedical and clinical research.


Center for Molecular Medicine Foundation, org. nr. 815201-3689

Karolinska University Hospital L8:05

Visionsgatan 18

171 76 Stockholm, Sweden


Karolinska institutet
Karolinska universitetssjukhuset