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Rare diseases research group


A rare disease is defined as a disease that affects fewer than 1 in 2,000 individuals. There are more than 6000 different rare diseases, affecting 6-8% or about 300 million people in the world. More than 80% are genetic and they are often complex and highly disabling. Only 5% of rare diseases have adequate treatments and the diseases lead to profound social and economic consequences. 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. Many lack 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.


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.


Research projects

Karolinska Undiagnosed Diseases Program (K-UDP) clinical site is located at Karolinska University laboratory where the Dep of Clinical genetics, is the clinical coordinating center, and Genomic Medicine Center Karolinska (GMCK), in collaboration with SciLifeLab, the sequencing core. The Rare Diseases research group is part of the Undiagnosed Diseases Network International (UDNI) - an international collaboration with research sites worldwide that work with the purpose to bring together clinical and research experts from across the world to solve the most challenging medical mysteries using advanced technologies. The UDP concept requires international collaboration and multidisciplinary one-stop shop outpatient clinics for diagnostics of patients with rare diseases of all ages.

The rare diseases group takes part in two European Reference Networks (ERNs): ITHACA (congenital malformations and rare intellectual disability) and BOND (Rare Bone Disorders) as well as Solve-RD – A H2020 funded five-year project that aims to identify diagnosis in unsolved patients.

We follow up on patients that are still undiagnosed after routine clinical evaluation and use bioinformatic reanalysis of whole genome sequencing (WGS) data where we also perform structural variant analysis (developed in house, see below) as well as other multi-omics approaches including RNA sequencing. We also participate in international projects where pooling of cases increases the chances of identifying causal variants. Functional evaluation of new candidate disease genes is performed in our own lab, in collaboration with the Metabolomics core at CMMS or other research groups working with model organisms at KI, within UDNI, ERN or at other centers. First, we evaluate effects on expression and splicing patient cell lines using RT-PCR, qPCR and Western blotting.

Specific research projects are:

1. Gene discoveries and identification of novel mutational mechanisms

2. Cancer predisposition syndromes and familial childhood cancers

3. The role of structural genomic variation in human health and disease

4. Cognition, Behavior and Pedagogical strategies in Individuals with genetically defined subgroups of Neurodevelopmental syndromes

research proj

Gene discoveries and identification of novel mutational mechanisms

The rare disease group conducts translational research studies. We focus our efforts in the following major areas:

  • Intellectual disability and autism

  • Cancer predisposition syndromes and familial childhood cancers

  • 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 our multidisciplinary national and international collaboration, we will gain insights in fundamental disease generating pathways that may be transferred to common diseases such as neuropsychiatric disorders, sporadic malformations and cancer. 

In house 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 the iPS cells are induced into neuronal stem cells enabling studies of synaptic structure and plasticity, expression profiling and dissection of specific gene-associated functions 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 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 patients we use overexpression of wild type and mutated RNA, transient knock down (morpholinos) and stable knockdown (CRISPR/Cas9 mutagenesis).

Cancer predisposition syndromes and familial childhood cancers

Our research is directed at identifying human disease genes that predispose to childhood cancer. Precision medicine and preventive surveillance for early detection in patients with germline mutations and even presymptomatic treatment of healthy carriers are important new steps in modern medicine towards the ultimate goal of curing all childhood cancers. Our aim is to discover novel targets for therapy and to identify risk factors where treatment should be modified to avoid toxicity or therapy resistance and when genetic counselling should be offered the family. We will also contribute to the development of surveillance protocols, increase awareness of genetic predisposition and investigate the benefits of integrating germline sequencing into clinical practice in paediatric oncology.

In order to 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 and adult cancers, patients with rare syndromes or overgrowth who developed cancer and isolated syndromic cases who developed cancer in childhood. We perform a careful clinical and dysmorphological evaluation and we use different WGS approaches such as singleton WGS in silico panel analysis and Trio WGS analyses (mother, father and child) to compare germline variants with parental DNA and somatically mutated cancer genes. In addition, RNA seq (transcriptome), methylation studies and protein analyses will be used in some cases.

The project has been approved by the Nordic Society of Paediatric Haematology and Oncology (NOPHO) Board as a NOPHO study. 

gene disc
chldhood canc

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). When candidate genes are identified functional studies are performed as described above.


Cognition, Behavior and Pedagogical strategies in Individuals with genetically defined subgroups of Neurodevelopmental syndromes

Individuals with rare syndromes have unique needs and problems that are caused by the syndrome. Today, there are more than 700 known genetic causes behind intellectual disability (ID) and every diagnosis has its own symptomatology. For example, different behaviors are more common in individuals with specific diagnoses, such as severe mood swings in Smith-Magenis syndrome, increased appetite in Prader-Willis syndrome, severe anxiety in Williams syndrome and risk of depression and other mental illnesses in 22q11 deletion carriers. The underlying causes of psychological symptoms that occur in different syndromes are poorly investigated, which means that you cannot offer individuals with rare syndromes an optimal treatment. We want to explore gene-specific clinical, behavioral and cognitive phenotypes in children and adolescents with ID through measurements of cognitive profiles, behavior, eye tracking, adaptive functioning, quality of life, neuropsychiatric and psychiatric comorbidity and structural and functional brain MRI.

Our goal is to customize treatment and care and to develop appropriate supportive pedagogical tools for individuals with ID. We collaborate with other researchers at KI in the eyetracking and functional and structural MRI studies and with researchers at Chalmers who are working with Cognitive modeling using Artificial Intelligence (AI) to develop AI systems with basic forms of learning impairment in order to develop tailored pedagogical tools to solve problems in mathematics and logic that are solvable with limited cognitive resources.

The results from our studies will be influent not only at an individual level and in specific patient groups but also generate knowledge and pedagogical tools that can be applied across a wide range of diagnoses.


Selected publications

Grigelioniene G, Suzuki H, Taylan F, Mirzamohammadi F, Borochowitz Z, Ayturk U, Tzur S, Horemuzova E, Anna Lindstrand A, Mary Weis M, Grigelionis G, Hammarsjö A, Marsk E, Nordgren A, Nordenskjöld M, Eyre D, Warman M, Nishimura G, Sharp PA. Gain-of-function mutation of microRNA-140 in human skeletal dysplasia. Nature Medicine. 2019 Feb 25.

Eisfeldt J, Pettersson M, Vezzi F, Wincent J, Käller M, Gruselius J, Nilsson D, Syk Lundberg E, Carvalho CMB, Lindstrand A. Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements. PLoS Genet. 2019 Feb 8;15(2):e1007858.

Järviaho T, Zachariadis V, Tesi B, Chiang S, Bryceson YT, Möttönen M, Niinimäki R, Bang B, Rahikkala E, Taylan F, Uusimaa J, Harila-Saari A, Nordgren A. Microdeletion of 7p12.1p13, including IKZF1, causes intellectual impairment, overgrowth, and susceptibility to leukaemia. Br J Haematol. 2018 Jul 13. 

Pettersson M, Vaz R, Hammarsjö A, Eisfeldt J, Carvalho CMB, Hofmeister W, Tham E, Horemuzova E, Voss U, Nishimura G, Klintberg B, Nordgren A, Nilsson D, Grigelioniene G, Lindstrand A. Alu-Alu mediated intragenic duplications in IFT81 and MATN3 are associated with skeletal dysplasias. Human mutation. 2018 Oct;39(10):1456-1467.

Nazaryan-Petersen L, Eisfeldt J, Pettersson M, Lundin J, Nilsson D, Wincent J, Lieden A, Lovmar L, Ottosson J, Gacic J, Mäkitie O, Nordgren A, Vezzi F,  Wirta V, Käller M, Duelund Hjortshøj T, Jespersgaard C, Houssari R, Pignata L, Bak M, Tommerup N, Syk Lundberg E, Tümer Z, Lindstrand A. Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization. PLOS Genetics. 2018 Nov 12;14(11):e1007780.

Taylan F, Bang B, Öfverholm II, Tran AN, Heyman M, Barbany G, Zachariadis V, Nordgren A. Somatic Structural Alterations in Childhood Leukemia Can Be Backtracked in Neonatal Dried Blood Spots by Use of Whole-Genome Sequencing and Digital PCR. Clin Chem. 2018 Dec 5. 

Ferreira CR, Xia ZJ, Clément A, Parry DA, Davids M, Taylan F, Sharma P, Turgeon CT, Blanco-Sánchez B, Ng BG, Logan CV, Wolfe LA, Solomon BD, Cho MT, Douglas G, Carvalho DR, Bratke H, Haug MG, Phillips JB, Wegner J, Tiemeyer M, Aoki K; Undiagnosed Diseases Network; Scottish Genome Partnership, Nordgren A, Hammarsjö A, Duker AL, Rohena L, Hove HB, Ek J, Adams D, Tifft CJ, Onyekweli T, Weixel T, Macnamara E, Radtke K, Powis Z, Earl D, Gabriel M, Russi AHS, Brick L, Kozenko M, Tham E, Raymond KM, Phillips JA 3rd, Tiller GE, Wilson WG, Hamid R, Malicdan MCV, Nishimura G, Grigelioniene G, Jackson A, Westerfield M, Bober MB, Gahl WA, Freeze HH. A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation. Am J Hum Genet. 2018 Oct 4;103(4):553-567. 

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

Stessman, H. A., B. Xiong, B. P. Coe, T. Wang, K. Hoekzema, M. Fenckova, M. Kvarnung, J. Gerdts, S. Trinh, N. Cosemans, L. Vives, J. Lin, T. N. Turner, G. Santen, C. Ruivenkamp, M. Kriek, A. van Haeringen, E. Aten, K. Friend, J. Liebelt, C. Barnett, E. Haan, M. Shaw, J. Gecz, B. M. Anderlid, A. Nordgren, A. Lindstrand, C. Schwartz, R. F. Kooy, G. Vandeweyer, C. Helsmoortel, C. Romano, A. Alberti, M. Vinci, E. Avola, S. Giusto, E. Courchesne, T. Pramparo, K. Pierce, S. Nalabolu, D. G. Amaral, I. E. Scheffer, M. B. Delatycki, P. J. Lockhart, F. Hormozdiari, B. Harich, A. Castells-Nobau, K. Xia, H. Peeters, M. Nordenskjold, A. Schenck, R. A. Bernier and E. E. Eichler. Targeted Sequencing Identifies 91 Neurodevelopmental-Disorder Risk Genes with Autism and Developmental-Disability Biases. Nature Genetics 2017 Apr;49(4):515-526.

Nilsson D, Pettersson M, Gustavsson P, Forster A, Hofmeister W, Wincent J, V. Zachariadis, B. M. Anderlid, A. Nordgren, O. Makitie, V. Wirta, M. Kaller, F. Vezzi, J. R. Lupski, M. Nordenskjold, E. Syk Lundberg, C. M. Carvalho, and A. Lindstrand. 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 38, no.2 (Feb 2017):180-92.

Reijnders MR, Zachariadis V, Latour B, Jolly L, Mancini GM, Pfundt R, Wu KM, van Ravenswaaij-Arts CM, Veenstra-Knol HE, Anderlid BM, Wood SA, Cheung SW, Barnicoat A, Probst F, Magoulas P, Brooks AS, Malmgren H, Harila-Saari A, Marcelis CM, Vreeburg M, Hobson E, Sutton VR, Stark Z, Vogt J, Cooper N, Lim JY, Price S, Lai AH, Domingo D, Reversade B, DDD Study, Gecz J, Gilissen C, Brunner HG, Kini U, Roepman R, Nordgren A°, Kleefstra T°. (°shared last authors). De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations. Am J Hum Genet. 2016 Feb;98(2) 373-381. 

Lindstrand A, Frangakis S, Carvalho CMB, Richardson EB, McFadden KA, Willer JR, Pehlivan D, Liu P, Pediaditakis IL, Sabo A, Lewis RA, Banin E, Lupski JR, Davis EE and Katsanis N (2016). Copy Number Variation Contributes to the Mutational Load of Bardet–Biedl syndrome. American Journal of Human Genetics, 2016 Aug 4;99(2):318-36.

Tham E, Lindstrand A, Santani A, Malmgren H, Nesbitt A, Dubbs HA, Zackai EH, Parker MJ, Millan F, Rosenbaum K, Wilson GN, Nordgren A. Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features. Am J Hum Genet. 2015 Mar;96(3) 507-513. 

Acuna-Hidalgo R*, Schanze D*, Kariminejad A*, Nordgren A*, Kariminejad MH, Conner P, Grigelioniene G, Nilsson D, Nordenskjöld M, Wedell A, Freyer C, Wredenberg A, Wieczorek D, Gillessen-Kaesbach G, Kayserili H, Elcioglu N, Ghaderi-Sohi S, Goodarzi P, Setayesh H, van de Vorst M, Steehouwer M, Pfundt R, Krabichler B, Curry C, MacKenzie MG, Boycott KM, Gilissen C, Janecke AR, Hoischen A, Zenker M (*shared first authors). Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. Am J Hum Genet. 2014 Sep;95(3) 285-293

Paulsson K, Lilljebjörn H, Biloglav A, Olsson L, Rissler M, Castor A, Barbany G, Fogelstrand L, Nordgren A, Sjögren H, Fioretos T, Johansson B. The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Nat Genet. 2015 Jun;47(6) 672-676. 

Helsmoortel C, Vulto-van Silfhout AT, Coe BP, Vandeweyer G, Rooms L, van den Ende J, Schuurs-Hoeijmakers JH, Marcelis CL, Willemsen MH, Vissers LE, Yntema HG, Bakshi M, Wilson M, Witherspoon KT, Malmgren H, Nordgren A, Annerén G, Fichera M, Bosco P, Romano C, de Vries BB, Kleefstra T, Kooy RF, Eichler EE, Van der Aa N. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat Genet. 2014 Apr;46(4) 380-384. 

Zachariadis V, Schoumans J, Ofverholm I, Barbany G, Halvardsson E, Forestier E, Johansson B, Nordenskjöld M, Nordgren A. Detecting dic(9;20)(p13.2;p11.2)-positive B-cell precursor acute lymphoblastic leukemia in a clinical setting using fluorescence in situ hybridization. Leukemia. 2014 Jan;28(1) 196-198. 

Lindstrand A, Grigelioniene G, Nilsson D, Pettersson M, Hofmeister W, Anderlid BM, Kant SG, Ruivenkamp CA, Gustavsson P, Valta H, Geiberger S, Topa A, Lagerstedt-Robinson K, Taylan F, Wincent J, Laurell T, Pekkinen M, Nordenskjöld M, Mäkitie O, Nordgren A. Different mutations in PDE4D associated with developmental disorders with mirror phenotypes. J Med Genet. 2014 Jan;51(1) 45-54.


Kvarnung M#, Nilsson D#, LINDSTRAND A# (# Shared 1st author), Korenke GC, Chiang SC, Blennow E, Bergmann M, Stodberg T, Makitie O, Anderlid BM, Bryceson YT, Nordenskjold M, Nordgren A. 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.

Laurell T, Vandermeer JE, Wenger AM, Grigelioniene G, Nordenskjöld A, Arner M, Ekblom AG, Bejerano G, Ahituv N, Nordgren A. A novel 13 base pair insertion in the sonic hedgehog ZRS limb enhancer (ZRS/LMBR1) causes preaxial polydactyly with triphalangeal thumb. Hum Mutat. 2012 Jul;33(7) 1063-1066. 

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