Eirik Frengen

• Awamleh, Zain; Chen, Anthony; Choufani, Sanaa; Rots, Dmitrijs; Ko, Jung Min & Armour, Christine M. [Show all 25 contributors for this article] (2026). KMT2A and KMT2B episignatures address diagnostic challenges associated with rare neurodevelopmental disorders. Genetics in Medicine. ISSN 1098-3600. 28(10). doi: 10.1016/j.gim.2026.102636. Full text in Research Archive
• Misceo, Doriana; Strømme, Petter; Sundaram, Arvind; Bjørnstad, Pål Marius; Strand, Mari Elen & Chawla, Maninder Singh [Show all 7 contributors for this article] (2026). A Homozygous Deep Intronic SNX14 Variant Activates Pseudo-Exon Inclusion in a Patient with SCAR20. Genes. 17(4). doi: 10.3390/genes17040378. Full text in Research Archive Show summary

  Background: The contribution of intronic variants to the etiology of Mendelian diseases is still underrecognized, impacting the diagnostic yield. Whole genome sequencing (WGS) detects intronic variants, but besides canonical splice-sites, intronic variants are frequently excluded from the interpretation step or are classified as variants of uncertain significance (VUS). In fact, assessing their clinical significance often requires validation via RNA-sequencing (RNA-seq) or in vitro studies. Methods: We studied a 31-year-old patient with spinocerebellar ataxia who lacked a molecular diagnosis after WGS analysis. We applied the Detection of RNA Outliers Pipeline (DROP) to analyze RNA-seq data from patient fibroblasts. DROP integrates OUTRIDER and FRASER 2.0 algorithms designed to identify aberrant gene expression and splicing, respectively. Results: DROP identified differential expression and aberrant splicing of SNX14. Retrospective WGS data analysis revealed a homozygous NM_153816.6(SNX14): c.867+288A>G deep intronic variant, which caused pseudo-exon activation and reduced transcript levels. Biallelic loss-of-function variants in SNX14 cause autosomal recessive spinocerebellar ataxia type 20 (SCAR20; OMIM 616354), consistent with the clinical presentation of this case. Conclusions: We identify a deep intronic SNX14 variant as the genetic basis of SCAR20. We demonstrate the utility of RNA-seq to increase the diagnostic yield by identifying and resolving the pathogenicity of deep intronic variants. Defining aberrant splicing events is therapeutically relevant, as these mechanisms are targets for antisense oligonucleotide (ASO) based interventions.

• Canavati, Christina; Oppebøen, Mari; Verma, Radha; Misceo, Doriana; Frengen, Eirik & Salvador, Cathrin Lytomt [Show all 29 contributors for this article] (2026). Biallelic SUPT4H1 variants cause a multisystem neurodevelopmental disorder associated with disrupted transcription. Genetics in Medicine. ISSN 1098-3600. 28(5). doi: 10.1016/j.gim.2026.102553. Full text in Research Archive Show summary

  Purpose We aimed to define the clinical and genetic basis of an autosomal recessive neurodevelopmental disorder identified in 3 unrelated families with an overlapping multisystem phenotype. Methods Exome or genome sequencing was performed in 6 affected individuals from 3 families, revealing biallelic variants in SUPT4H1. Functional effects were evaluated using CRISPR and RNAi knockdown in C. elegans. Transcriptomic and proteomic profiling were conducted on patient-derived fibroblasts. Phylogenetic profiling assessed evolutionary conservation and coevolution. Dopamine response was evaluated in 2 affected siblings. Results All individuals carried biallelic SUPT4H1 variants—1 frameshift and 2 missense variants. Shared features included intellectual disability, dystonia, speech impairment, craniofacial dysmorphism, skeletal anomalies, and enamel hypoplasia. Functional modeling in C. elegans confirmed pathogenicity through neuromotor deficits. Multiomics analyses revealed dysregulation of developmental gene networks and the transcriptional machinery with disrupted RNA polymerase complexes and cell-cycle regulators. Dopamine treatment improved motor symptoms and normalized cerebrospinal neurotransmitter levels in 2 siblings. Conclusion Biallelic variants in SUPT4H1 cause a previously unrecognized multisystem neurodevelopmental disorder. These findings underscore the importance of disrupted transcription in human disease and demonstrate how integrated multiomics and cross-species modeling can reveal underlying mechanisms and provide a foundation for future studies of transcriptional regulation.

• Misceo, Doriana; Terkelsen, Thorkild; Keim, Sara; Bjørnstad, Pål Marius; Strand, Mari Elen & Orszagh, Vivian C [Show all 8 contributors for this article] (2025). CRISPR Activation Reveals the Spliceogenicity of an Intronic NEB Variant in Fetuses With Arthrogryposis Multiplex Congenita 6. Clinical Genetics. ISSN 0009-9163. 109(4), p. 772–777. doi: 10.1111/cge.70097. Full text in Research Archive Show summary

  Whole-genome sequencing identifies intronic variants whose pathogenicity can be predicted with tools like SpliceAI. However, an actionable classification of such variants may require RNA-based validation, which can be limited by low expression in clinically accessible tissues. We report two fetuses from one family with Arthrogryposis multiplex congenita 6 (AMC6 [OMIM # 619334]) and biallelic NEB variants: a paternally inherited likely pathogenic frameshift variant, Chr2(GRCh38):g.151579391del; NM_001164508.2:c.16653del; NP_001157980.2:p.(Asp5552ThrfsTer5), and a maternally inherited intronic variant of uncertain clinical significance, Chr2(GRCh38):g.151496267G>A; NM_001164508.2:c.24486+9C>T; NP_001157980.2:p.(?). Because NEB is poorly expressed in fibroblasts, we used CRISPR activation to induce its expression in fibroblasts from the heterozygous mother. RNA-sequencing subsequently confirmed that the intronic variant generated a novel splice donor site associated with inferred loss of splicing at the canonical donor site. After NMD-inhibition, we could thus identify 45.5% of NEB transcripts with a 7 bp exon extension, predicted to result in a protein-coding frameshift. The intronic variant was classified as likely pathogenic, allowing a genetic diagnosis.

• Hynes, Claire; Williams, Evan; Misceo, Doriana; Strømme, Petter; Frengen, Eirik & Kakumani, Pavan Kumar (2025). De novo CSDE1 missense variant T595N regulates miRNA expression in a patient with a complex neurodevelopmental condition. Biochimica et Biophysica Acta - Molecular Basis of Disease. ISSN 0925-4439. 1872(3). doi: 10.1016/j.bbadis.2025.168104. Full text in Research Archive Show summary

  • Loss of function variants in CSDE1 have been identified in patients with neurodevelopmental disorders. • De novo CSDE1 missense variant T595N was identified in an individual manifesting autistic behavior in addition to features typical of Cohen syndrome. • Patient derived skin fibroblasts expressing T595N showed increased expression of HECW2. • HECW2 is a ubiquitin ligase associated with neurodevelopment, and a synapse-related target of CSDE1. • The E3 ligase activity of HECW2 is necessary for the downregulation of Dicer protein, a core component in the miRNA pathway that dictates miRNA expression.

• Misceo, Doriana; Strømme, Petter; Bitarafan, Fatemeh; Chawla, Maninder Singh; Sheng, Ying & Courtade, Sandra Monica Bach de [Show all 8 contributors for this article] (2024). Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome. Genes. 15:500(4), p. 1–10. doi: 10.3390/genes15040500. Full text in Research Archive Show summary

  Oxidative phosphorylation involves a complex multi-enzymatic mitochondrial machinery critical for proper functioning of the cell, and defects herein cause a wide range of diseases called “primary mitochondrial disorders” (PMDs). Mutations in about 400 nuclear and 37 mitochondrial genes have been documented to cause PMDs, which have an estimated birth prevalence of 1:5000. Here, we describe a 4-year-old female presenting from early childhood with psychomotor delay and white matter signal changes affecting several brain regions, including the brainstem, in addition to lactic and phytanic acidosis, compatible with Leigh syndrome, a genetically heterogeneous subgroup of PMDs. Whole genome sequencing of the family trio identified a homozygous 12.9 Kb deletion, entirely overlapping the NDUFA4 gene. Sanger sequencing of the breakpoints revealed that the genomic rearrangement was likely triggered by Alu elements flanking the gene. NDUFA4 encodes for a subunit of the respiratory chain Complex IV, whose activity was significantly reduced in the patient’s fibroblasts. In one family, dysfunction of NDUFA4 was previously documented as causing mitochondrial Complex IV deficiency nuclear type 21 (MC4DN21, OMIM 619065), a relatively mild form of Leigh syndrome. Our finding confirms the loss of NDUFA4 function as an ultra-rare cause of Complex IV defect, clinically presenting as Leigh syndrome.

• Ghaffar, Amama; Akhter, Tehmeena; Strømme, Petter; Misceo, Doriana; Khan, Amjad & Frengen, Eirik [Show all 22 contributors for this article] (2024). Variants of NAV3, a neuronal morphogenesis protein, cause intellectual disability, developmental delay, and microcephaly. Communications Biology. 7(1). doi: 10.1038/s42003-024-06466-1. Full text in Research Archive Show summary

  Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.

• Gamage, Thilini Hansamali Gamage Yaddehi; Grabmayr, Herwig; Horvath, Ferdinand; Fahrner, Marc; Misceo, Doriana & Louch, William Edward [Show all 21 contributors for this article] (2023). A single amino acid deletion in the ER Ca2+ sensor STIM1 reverses the in vitro and in vivo effects of the Stormorken syndrome-causing R304W mutation. Science Signaling. ISSN 1945-0877. 16(771). doi: 10.1126/scisignal.add0509. Full text in Research Archive
• Misceo, Doriana; Lirussi, Lisa; Strømme, Petter; Sumathipala, Dulika Sanjeewani; Guerin, Andrea & Wolf, Nicole I [Show all 14 contributors for this article] (2023). A homozygous POLR1A variant causes leukodystrophy and affects protein homeostasis. Brain. ISSN 0006-8950. 146(8), p. 3513–3527. doi: 10.1093/brain/awad086. Full text in Research Archive Show summary

  Abstract RNA polymerase I transcribes ribosomal DNA to produce precursor 47S rRNA. Post-transcriptional processing of this rRNA generates mature 28S, 18S and 5.8S rRNAs, which form the ribosomes, together with 5S rRNA, assembly factors and ribosomal proteins. We previously reported a homozygous variant in the catalytic subunit of RNA polymerase I, POLR1A, in two brothers with leukodystrophy and progressive course. However, the disease mechanism remained unknown. In this report, we describe another missense variant POLR1A NM_015425.3:c.1925C>A; p.(Thr642Asn) in homozygosity in two unrelated patients. Patient 1 was a 16-year-old male and Patient 2 was a 2-year-old female. Both patients manifested neurological deficits, with brain MRIs showing hypomyelinating leukodystrophy and cerebellar atrophy; and in Patient 1 additionally with hypointensity of globi pallidi and small volume of the basal ganglia. Patient 1 had progressive disease course, leading to death at the age of 16.5 years. Extensive in vitro experiments in fibroblasts from Patient 1 documented that the mutated POLR1A led to aberrant rRNA processing and degradation, and abnormal nucleolar homeostasis. Proteomics data analyses and further in vitro experiments documented abnormal protein homeostasis, and endoplasmic reticulum stress responses. We confirm that POLR1A biallelic variants cause neurodegenerative disease, expand the knowledge of the clinical phenotype of the disorder, and provide evidence for possible pathological mechanisms leading to POLR1A-related leukodystrophy.

• Misceo, Doriana; Senaratne, Lokuliyanage Dona Samudita; Mero, Inger-Lise; Sundaram, Arvind; Bjørnstad, Pål Marius & Szczałuba, Krzysztof [Show all 12 contributors for this article] (2023). Novel Loss of Function Variants in CENPF Including a Large Intragenic Deletion in Patients with Strømme Syndrome. Genes. 14(11), p. 1–11. doi: 10.3390/genes14111985. Full text in Research Archive Show summary

  Strømme syndrome is an ultra-rare primary ciliopathy with clinical variability. The syndrome is caused by bi-allelic variants in CENPF, a protein with key roles in both chromosomal segregation and ciliogenesis. We report three unrelated patients with Strømme syndrome and, using high-throughput sequencing approaches, we identified novel pathogenic variants in CENPF, including one structural variant, giving a genetic diagnosis to the patients. Patient 1 was a premature baby who died at 26 days with congenital malformations affecting many organs including the brain, eyes, and intestine. She was homozygous for a donor splice variant in CENPF, NM_016343.3:c.1068+1G>A, causing skipping of exon 7, resulting in a frameshift. Patient 2 was a female with intestinal atresia, microcephaly, and a Peters anomaly. She had normal developmental milestones at the age of 7 years. She is compound heterozygous for CENPF NM_016343.3:c.5920dup and c.8991del, both frameshift. Patient 3 was a male with anomalies of the brain, eye, intestine, and kidneys. He was compound heterozygous for CENPF p.(Glu298Ter), and a 5323 bp deletion covering exon 1. CENPF exon 1 is flanked by repetitive sequences that may represent a site of a recurrent structural variation, which should be a focus in patients with Strømme syndrome of unknown etiology.

• Saida, Ken; Maroofian, Reza; Sengoku, Toru; Mitani, Tadahiro; Pagnamenta, Alistair T. & Marafi, Dana [Show all 87 contributors for this article] (2022). Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals. Genetics in Medicine. ISSN 1098-3600. 25(1), p. 90–102. doi: 10.1016/j.gim.2022.09.010. Full text in Research Archive
• Cherik, Florian; Reilly, Jack; Kerkhof, Jennifer; Levy, Michael; McConkey, Haley & Barat-Houari, Mouna [Show all 34 contributors for this article] (2022). DNA methylation episignature in Gabriele-de Vries syndrome. Genetics in Medicine. ISSN 1098-3600. 24(4), p. 905–914. doi: 10.1016/j.gim.2021.12.003. Full text in Research Archive
• Sumathipala, Dulika Sanjeewani; Strømme, Petter; Fattahi, Zohreh; Lüders, Torben; Sheng, Ying & Kahrizi, Kimia [Show all 20 contributors for this article] (2022). ZBTB11 dysfunction: Spectrum of brain abnormalities, biochemical signature and cellular consequences. Brain. ISSN 0006-8950. 145(7), p. 2602–2616. doi: 10.1093/brain/awac034. Full text in Research Archive Show summary

  Abstract Bi-allelic pathogenic variants in ZBTB11 have been associated with intellectual developmental disorder, autosomal recessive 69 (MRT69; OMIM 618383). We report five patients from three families with novel, bi-allelic variants in ZBTB11. We have expanded the clinical phenotype of MRT69, documenting varied severity of atrophy affecting different brain regions and described combined malonic and methylmalonic aciduria as a biochemical manifestation. As ZBTB11 encodes for a transcriptional regulator, we performeded chromatin immunoprecipitation–sequencing targeting ZBTB11 in fibroblasts from patients and controls. Chromatin immunoprecipitation–sequencing revealed binding of wild-type ZBTB11 to promoters in 238 genes, among which genes encoding proteins involved in mitochondrial functions and RNA processing are over-represented. Mutated ZBTB11 showed reduced binding to 61 of the targeted genes, indicating that the variants act as loss of function. Most of these genes are related to mitochondrial functions. Transcriptome analysis of the patient fibroblasts revealed dysregulation of mitochondrial functions. In addition, we uncovered that reduced binding of the mutated ZBTB11 to ACSF3 leads to decreased ACSF3 transcript level, explaining combined malonic and methylmalonic aciduria. Collectively, these results expand the clinical spectrum of ZBTB11-related neurological disease and give insight into the pathophysiology in which the dysfunctional ZBTB11 affect mitochondrial functions and RNA processing contributing to the neurological and biochemical phenotypes.

• Slavotinek, Anne; Misceo, Doriana; Htun, Stephanie; Mathisen, Linda; Frengen, Eirik & Foreman, Michelle [Show all 23 contributors for this article] (2020). Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness. Human Molecular Genetics. ISSN 0964-6906. 29(13), p. 2218–2239. doi: 10.1093/hmg/ddaa108. Full text in Research Archive Show summary

  Abstract The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. While we ascertained five patients, three patients with distinct variants of EXOSC5 were studied in detail. The first patient had a deletion involving exons 5–6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. The additional two patients ascertained are siblings who had an early frameshift mutation in EXOSC5 and the p.Thr114Ile missense variant that were inherited in trans. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess consequences of pathogenic EXOSC5 variants. Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. These findings expand the number of genes encoding RNA exosome subunits linked to human disease while also suggesting that disease mechanism varies depending on the specific pathogenic variant.

• Sumathipala, Dulika Sanjeewani; Strømme, Petter; Gilissen, Christian; Einarsen, Ingunn Holm; Bjørndalen, Hilde & Server, Andrés [Show all 11 contributors for this article] (2020). Sudden death in epilepsy and ectopic neurohypophysis in Joubert syndrome 23 diagnosed using SNVs/indels and structural variants pipelines on WGS data: a case report. BMC Medical Genetics. 21:96, p. 1–6. doi: 10.1186/s12881-020-01024-y. Full text in Research Archive Show summary

  Background Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. Case presentation Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. Conclusions We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.

• Cogne, Benjamin; Latypova, Xénia; Senaratne, Lokuliyanage Dona Samudita; Martin, Ludovic; Koboldt, Daniel C. & Kellaris, Georgios [Show all 28 contributors for this article] (2020). Mutations in the Kinesin-2 motor KIF3B cause an Autosomal-Dominant Ciliopathy. American Journal of Human Genetics. ISSN 0002-9297. 106(6), p. 893–904. doi: 10.1016/j.ajhg.2020.04.005. Full text in Research Archive Show summary

  Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity isdriven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exomesequencing, we identified heterozygousKIF3Bvariants in two unrelated families with hallmark ciliopathy phenotypes. In the first fam-ily, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors ade novoc.748G>C(p.Glu250Gln) variant affecting the kinesin motor domain encoded byKIF3B. The second family is a six-generation pedigree affectedpredominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro)KIF3Bvariant segregatingin an autosomal-dominant pattern. We observed a significant increase in primary cilia lengthin vitroin the context of either of the twomutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects ofKIF3Bmutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered tothe photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin traf-ficking is also characteristic of recessiveKIF3Bmodels as exemplified by an early-onset, autosomal-recessive, progressive retinal degen-eration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr)KIF3Bvariant by genome-wide association study and whole-genomesequencing. Together, our genetic, cell-based, andin vivomodeling data delineate an autosomal-dominant syndromic retinal ciliopathyin humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor

• Sumathipala, Dulika Sanjeewani; Misceo, Doriana; Larsen, Selma Mujezinovic; Barøy, Tuva; Gamage, Thilini H. & Frengen, Eirik [Show all 7 contributors for this article] (2020). A girl with a neurodevelopmental syndrome, adducted thumbs and frequent infections caused by novel homozygous variant in DEAF1. Clinical Dysmorphology. ISSN 0962-8827. 29(2), p. 107–110. doi: 10.1097/MCD.0000000000000314. Full text in Research Archive
• Chen, Chun-An; Crutcher, Emeline; Gill, Harinder; Nelson, Tanya N.; Robak, Laurie A. & Jongmans, Marjolijn C.J. [Show all 18 contributors for this article] (2020). The expanding clinical phenotype of germline ABL1-associated congenital heart defects and skeletal malformations syndrome. Human Mutation. ISSN 1059-7794. 41(10), p. 1738–1744. doi: 10.1002/humu.24075. Full text in Research Archive Show summary

  Congenital heart defects and skeletal malformations syndrome (CHDSKM) is a rareautosomal dominant disorder characterized by congenital heart disease, skeletalabnormalities, and failure to thrive. CHDSKM is caused by germline mutations inABL1. To date, three variants have been in association with CHDSKM. In this study,we describe three de novo missense variants, c.407C>T (p.Thr136Met), c.746C>T(p.Pro249Leu), and c.1573G>A (p.Val525Met), and one recurrent variant,c.1066G>A (p.Ala356Thr), in six patients, thereby expanding the phenotypic spec-trum of CHDSKM to include hearing impairment, lipodystrophylike features, renalhypoplasia, and distinct ocular abnormalities. Functional investigation of the three novel variants showed an increased ABL1 kinase activity. The cardiac findings in additional patients with p.Ala356Thr contribute to the accumulating evidence that patients carrying either one of the recurrent variants, p.Tyr245Cys and p.Ala356Thr, have a high incidence of cardiac abnormalities.The phenotypic expansion has implications for the clinical diagnosis of CHDSKM in patients with germline ABL1 variants.

• Epting, Daniel; Senaratne, Lokuliyanage Dona Samudita; Ott, Elisabeth; Holmgren, Asbjørn; Sumathipala, Dulika Sanjeewani & Larsen, Selma Mujezinovic [Show all 30 contributors for this article] (2020). Loss of CBY1 results in a ciliopathy characterized by features of Joubert syndrome. Human Mutation. ISSN 1059-7794. p. 1–16. doi: 10.1002/humu.24127. Full text in Research Archive
• Gamage, Thilini Hansamali Gamage Yaddehi; Lengle, Emma; Gunnes, Gjermund; Pullisaar, Helen; Holmgren, Asbjørn & Reseland, Janne Elin [Show all 16 contributors for this article] (2019). STIM1 R304W in mice causes subgingival hair growth and an increased fraction of trabecular bone. Cell Calcium. ISSN 0143-4160. 85. doi: 10.1016/j.ceca.2019.102110. Full text in Research Archive
• Gamage, Thilini Hansamali Gamage Yaddehi; Gunnes, Gjermund; Lee, Robert Hugh; Louch, William Edward; Holmgren, Asbjørn & Bruton, Joseph D. [Show all 19 contributors for this article] (2018). STIM1 R304W causes muscle degeneration and impaired platelet activation in mice. Cell Calcium. ISSN 0143-4160. 76, p. 87–100. doi: 10.1016/j.ceca.2018.10.001. Full text in Research Archive Show summary

  STIM1 and ORAI1 regulate store-operated Ca2+ entry (SOCE) in most cell types, and mutations in these proteins have deleterious and diverse effects. We established a mouse line expressing the STIM1 R304 W gain-of-function mutation causing Stormorken syndrome to explore effects on organ and cell physiology. While STIM1 R304 W was lethal in the homozygous state, surviving mice presented with reduced growth, skeletal muscle degeneration, and reduced exercise endurance. Variable STIM1 expression levels between tissues directly impacted cellular SOCE capacity. In contrast to patients with Stormorken syndrome, STIM1 was downregulated in fibroblasts from Stim1R304W/R304W mice, which maintained SOCE despite constitutive protein activity. In studies using foetal liver chimeras, STIM1 protein was undetectable in homozygous megakaryocytes and platelets, resulting in impaired platelet activation and absent SOCE. These data indicate that downregulation of STIM1 R304 W effectively opposes the gain-of-function phenotype associated with this mutation, and highlight the importance of STIM1 in skeletal muscle development and integrity.

• Strømme, Petter; Groeneweg, Stefan; Souza, Elaine C. Lima de; Zevenbergen, Chantal; Torgersbråten, Anette & Holmgren, Asbjørn [Show all 17 contributors for this article] (2018). Mutated thyroid hormone transporter OATP1C1 associates with severe brain hypometabolism and juvenile neurodegeneration. Thyroid. ISSN 1050-7256. 28(11), p. 1406–1415. doi: 10.1089/thy.2018.0595. Full text in Research Archive Show summary

  Background: Thyroid hormones (TH) are essential for brain development and function. The TH transporters monocarboxylate transporter 8 (MCT8) and organic anion transporter1 C1 (OATP1C1) facilitate the transport of TH across the blood–brain barrier and into glia and neuronal cells in the brain. Loss of MCT8 function causes Allan–Herndon–Dudley syndrome (AHDS, OMIM 300523) characterized by severe intellectual and motor disability due to cerebral hypothyroidism. Here, the first patient with loss of OATP1C1 function is described. The patient is a 15.5-year-old girl with normal development in the first year of life, who gradually developed dementia with spasticity and intolerance to cold. Brain imaging demonstrated gray and white matter degeneration and severe glucose hypometabolism. Methods: Exome sequencing of the patient and parents was performed to identify the disease-causing mutation, and the effect of the mutation was studied through a panel of in vitro experiments, including thyroxine uptake studies, immunoblotting, and immunocytochemistry. Furthermore, the clinical effects of treatment with the triiodothyronine analogue triiodothyroacetic acid (Triac) are described. Results: Exome sequencing identified a homozygous missense mutation in OATP1C1, changing the highly conserved aspartic acid 252 to asparagine (D252N). In vitro, the mutated OATP1C1 displays impaired plasma membrane localization and decreased cellular thyroxine uptake. After treatment with Triac, the clinical condition improved in several domains. Conclusions: This is the first report of human OATP1C1 deficiency compatible with brain-specific hypothyroidism and neurodegeneration.

• Kotlarz, Daniel; Marquardt, Benjamin; Barøy, Tuva; Lee, Way S.; Konnikova, Liza & Hollizeck, Sebastian [Show all 24 contributors for this article] (2018). Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy. Nature Genetics. ISSN 1061-4036. 50(3), p. 344–348. doi: 10.1038/s41588-018-0063-6. Full text in Research Archive Show summary

  Transforming growth factor (TGF)-β1 (encoded by TGFB1) is the prototypic member of the TGF-β family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis1,2. Following its discovery3, enormous interest and numerous controversies have emerged about the role of TGF-β in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti-inflammatory effects6, or pro- and anti-fibrinogenic characteristics7. Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-β1–LAP complex, which is suggestive of perturbed bioavailability of TGF-β1. Our study shows that TGF-β1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.

• Platzer, Konrad; Yuan, Hongjie; Schütz, Hannah; Winschel, Alexander; Chen, Wenjuan & Hu, Chun [Show all 75 contributors for this article] (2017). GRIN2B encephalopathy: Novel findings on phenotype, variant clustering, functional consequences and treatment aspects. Journal of Medical Genetics. ISSN 0022-2593. 54(7), p. 460–470. doi: 10.1136/jmedgenet-2016-104509. Full text in Research Archive Show summary

  Background: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. Methods: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. Results: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. Conclusions: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.

• Gabriele, Michele; Silfhout, Anneke T. Vulto-van; Germain, Pierre-Luc; Vitriolo, Alessandro; Kumar, Raman & Douglas, Evelyn [Show all 51 contributors for this article] (2017). YY1 haploinsufficiency causes an intellectual disability syndrome featuring transcriptional and chromatin dysfunction. American Journal of Human Genetics. ISSN 0002-9297. 100(6), p. 907–925. doi: 10.1016/j.ajhg.2017.05.006. Full text in Research Archive Show summary

  Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define “YY1 syndrome” as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals’ cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.

• Ansar, Muhammad; Riazuddin, Saima; Sarwar, Muhammad Tahir; Makrythanasis, Periklis; Paracha, Sohail Aziz & Iqbal, Zafar [Show all 26 contributors for this article] (2017). Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay. Genetics in Medicine. ISSN 1098-3600. 20(7), p. 778–784. doi: 10.1038/gim.2017.113. Full text in Research Archive Show summary

  Purpose: To elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability. Methods: A combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California–San Francisco Chimera software. Results: All five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein. Conclusion: LINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-of-function studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans.

• Barøy, Tuva; Jesuthasan, Christeen Ramane Pedurupillay; Bliksrud, Yngve Thomas; Rasmussen, Magnhild; Holmgren, Asbjørn & Vigeland, Magnus Dehli [Show all 13 contributors for this article] (2016). A novel mutation in FBXL4 in a Norwegian child with encephalomyopathic mitochondrial DNA depletion syndrome 13. European Journal of Medical Genetics. ISSN 1769-7212. 59(6-7), p. 342–346. doi: 10.1016/j.ejmg.2016.05.005. Full text in Research Archive
• Lemke, Johannes R.; Geider, Kirsten; Helbig, Katherine L.; Heyne, Henrike O.; Schutz, Hannah & Hentschel, Julia [Show all 58 contributors for this article] (2016). Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy. Neurology. ISSN 0028-3878. 86(23), p. 2171–2178. doi: 10.1212/WNL.0000000000002740. Full text in Research Archive
• Jesuthasan, Christeen Ramane Pedurupillay; Landsend, Erlend Christoffer Sommer; Vigeland, Magnus Dehli; Ansar, Muhammad; Frengen, Eirik & Misceo, Doriana [Show all 7 contributors for this article] (2016). Segregation of incomplete achromatopsia and alopecia due to PDE6H and LPAR6 variants in a consanguineous family from Pakistan. Genes. 7(8). doi: 10.3390/genes7080041. Full text in Research Archive Show summary

  We report on two brothers with visual impairment, and non-syndromic alopecia in the elder proband. The parents were first-degree Pakistani cousins. Whole exome sequencing of the elder brother and parents, followed by Sanger sequencing of all four family members, led to the identification of the variants responsible for the two phenotypes. One variant was a homozygous nonsense variant in the inhibitory subunit of the cone-specific cGMP phosphodiesterase gene, PDE6H:c.35C>G (p.Ser12*). PDE6H is expressed in the cones of the retina, which are involved in perception of color vision. This is the second report of a homozygous PDE6H:c.35C>G variant causing incomplete achromatopsia (OMIM 610024), thus strongly supporting the hypothesis that loss-of-function variants in PDE6H cause this visual deficiency phenotype. The second variant was a homozygous missense substitution in the lysophosphatidic acid receptor 6, LPAR6:c.188A>T (p.Asp63Val). LPAR6 acts as a G-protein-coupled receptor involved in hair growth. Biallelic loss-of-function variants in LPAR6 cause hypotrichosis type 8 (OMIM 278150), with or without woolly hair, a form of non-syndromic alopecia. Biallelic LPAR6:c.188A>T was previously described in five families from Pakistan.

• Skauli, Nadia; Wallace, Sean Ciaran; Chiang, Samuel C.C.; Barøy, Tuva; Holmgren, Asbjørn & Stray-Pedersen, Asbjørg [Show all 10 contributors for this article] (2016). Novel PIGT Variant in Two Brothers: Expansion of the Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 Phenotype. Genes. 7(12). doi: 10.3390/genes7120108. Full text in Research Archive Show summary

  Biallelic PIGT variants were previously reported in seven patients from three families with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3), characterized by epileptic encephalopathy, hypotonia, global developmental delay/intellectual disability, cerebral and cerebellar atrophy, craniofacial dysmorphisms, and skeletal, ophthalmological, cardiac, and genitourinary abnormalities. We report a novel homozygous PIGT missense variant c.1079G>T (p.Gly360Val) in two brothers with several of the typical features of MCAHS3, but in addition, pyramidal tract neurological signs. Notably, they are the first patients with MCAHS3 without skeletal, cardiac, or genitourinary anomalies. PIGT encodes a crucial subunit of the glycosylphosphatidylinositol (GPI) transamidase complex, which catalyzes the attachment of proteins to GPI-anchors, attaching the proteins to the cell membrane. In vitro studies in cells from the two brothers showed reduced levels of GPI-anchors and GPI-anchored proteins on the cell surface, supporting the pathogenicity of the novel PIGT variant.

• Jesuthasan, Christeen Ramane Pedurupillay; Amundsen, Svanstrøm Silja; Barøy, Tuva; Rasmussen, Magnhild; Blomhoff, Anne & Stadheim, Barbro [Show all 12 contributors for this article] (2016). Clinical and molecular characteristics in three families with biallelic mutations in IGHMBP2. Neuromuscular Disorders. ISSN 0960-8966. 26(9), p. 570–575. doi: 10.1016/j.nmd.2016.06.457. Full text in Research Archive
• Hladilkova, Eva; Barøy, Tuva; Fannemel, Madeleine; Vallova, Vladimira; Misceo, Doriana & Bryn, Vesna [Show all 10 contributors for this article] (2015). A recurrent deletion on chromosome 2q13 is associated with developmental delay and mild facial dysmorphisms. Molecular Cytogenetics. 8:57. doi: 10.1186/s13039-015-0157-0. Full text in Research Archive Show summary

  We report two unrelated patients with overlapping chromosome 2q13 deletions (patient 1 in chr2:111415137-113194067 bp and patient 2 in chr2:110980342-113007823 bp, hg 19). Patient 1 presents with developmental delay, microcephaly and mild dysmorphic facial features, and patient 2 with autism spectrum disorder, borderline cognitive abilities, deficits in attention and executive functions and mild dysmorphic facial features. The mother and maternal grandmother of patient 1 were healthy carriers of the deletion. Previously, 2q13 deletions were reported in 27 patients, and the interpretation of its clinical significance varied. Our findings support that the 2q13 deletion is associated with a developmental delay syndrome manifesting with variable expressivity and reduced penetrance which poses a challenge for genetic counselling as well as the clinical recognition of 2q13 deletion patients.

• Tjeldhorn, Lena; Amundsen, Svanstrøm Silja; Barøy, Tuva; Rand-Hendriksen, Svend; Geiran, Odd & Frengen, Eirik [Show all 7 contributors for this article] (2015). Qualitative and quantitative analysis of FBN1 mRNA from 16 patients with Marfan Syndrome. BMC Medical Genetics. 16(113). doi: 10.1186/s12881-015-0260-4. Full text in Research Archive Show summary

  Background Pathogenic mutations in FBN1, encoding the glycoprotein, fibrillin-1, cause Marfan syndrome (MFS) and related connective tissue disorders. In the present study, qualitative and quantitative effects of 16 mutations, identified in FBN1 in MFS patients with systematically described phenotypes, were investigated in vitro. Methods Qualitative analysis was performed with reverse transcription-PCR (RT-PCR) and gel electrophoresis, and quantitative analysis to determine the FBN1 mRNA levels in fibroblasts from the 16 patients with MFS was performed with real-time PCR. Results Qualitative analysis documented that the mutations c.4817-2delA and c.A4925G led to aberrant FBN1 mRNA splicing leading to in frame deletion of exon 39 and in exon 39, respectively. No difference in the mean FBN1 mRNA level was observed between the entire group of cases and controls, nor between the group of patients with missense mutations and controls. The mean expression levels associated with premature termination codon (PTC) and splice site mutations were significantly lower than the levels in patients with missense mutations. A high level of FBN1 mRNA in the patient with the missense mutation c.G2447T did not segregate with the mutation in three of his first degree relatives. No association was indicated between the FBN1 transcript level and specific phenotypic manifestations. Conclusions Abnormal FBN1 transcripts were indicated in fibroblasts from patients with the splice site mutation c.4817-2delA and the missense mutation c.A4925G. While the mean FBN1 mRNA expression level in fibroblasts from patients with splice site and PTC mutations were lower than the mean level in patients with missense mutations and controls, inter-individual variability was high. The observation that high level of FBN1 mRNA in the patient with the missense mutation c.G2447T did not segregate with the mutation in the family suggests that variable expression of the normal FBN1 allele may contribute to explain the variability in FBN1 mRNA level.

• Barøy, Tuva; Koster, Janet; Strømme, Petter; Ebberink, Merel S.; Misceo, Doriana & Ferdinandusse, Sacha [Show all 18 contributors for this article] (2015). A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform. Human Molecular Genetics. ISSN 0964-6906. 24(20), p. 5845–5854. doi: 10.1093/hmg/ddv305. Full text in Research Archive
• Carlsen, Ellen Øen; Frengen, Eirik; Fannemel, Madeleine & Misceo, Doriana (2015). Haploinsufficiency of ANO6, NELL2 and DBX2 in a boy with intellectual disability and growth delay. American Journal of Medical Genetics. ISSN 0148-7299. 167(8), p. 1890–1896. doi: 10.1002/ajmg.a.37079. Full text in Research Archive
• Ramane, Pedurupillay Jesuthasan Christeen; Barøy, Tuva; Holmgren, Asbjørn; Blomhoff, Anne; Vigeland, Magnus Dehli & Sheng, Ying [Show all 9 contributors for this article] (2015). Kaufman oculocerebrofacial syndrome in sisters with novel compound heterozygous mutation in UBE3B. American Journal of Medical Genetics. Part A. ISSN 1552-4825. 167(3), p. 657–663. doi: 10.1002/ajmg.a.36944. Full text in Research Archive
• Fannemel, Madeleine; Barøy, Tuva; Holmgren, Asbjørn; Rødningen, Olaug Kristin; Haugsand, Trine Marie & Hansen, Børre [Show all 8 contributors for this article] (2014). Haploinsufficiency of XPO1 and USP34 by a de novo 230 kb deletion in 2p15, in a patient with mild intellectual disability and cranio-facial dysmorphisms. European Journal of Medical Genetics. ISSN 1769-7212. 57(9), p. 513–519. doi: 10.1016/j.ejmg.2014.05.008. Full text in Research Archive
• Wedding, Iselin Marie; Koht, Jeanette; Tran, Gia Tuong Thi; Misceo, Doriana; Selmer, Kaja Kristine & Holmgren, Asbjørn [Show all 10 contributors for this article] (2014). Spastic paraplegia type 7 is associated with multiple mitochondrial DNA deletions. PLOS ONE. 9(1). doi: 10.1371/journal.pone.0086340. Full text in Research Archive Show summary

  Spastic paraplegia 7 is an autosomal recessive disorder caused by mutations in the gene encoding paraplegin, a protein located at the inner mitochondrial membrane and involved in the processing of other mitochondrial proteins. The mechanism whereby paraplegin mutations cause disease is unknown. We studied two female and two male adult patients from two Norwegian families with a combination of progressive external ophthalmoplegia and spastic paraplegia. Sequencing of SPG7 revealed a novel missense mutation, c.2102A>C, p.H 701P, which was homozygous in one family and compound heterozygous in trans with a known pathogenic mutation c.1454_1462del in the other. Muscle was examined from an additional, unrelated adult female patient with a similar phenotype caused by a homozygous c.1047insC mutation in SPG7. Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV. Molecular studies in single, microdissected fibres showed multiple mitochondrial DNA deletions segregating at high levels (38–97%) in respiratory deficient fibres. Our findings demonstrate for the first time that paraplegin mutations cause accumulation of mitochondrial DNA damage and multiple respiratory chain deficiencies. While paraplegin is not known to be directly associated with the mitochondrial nucleoid, it is known to process other mitochondrial proteins and it is possible therefore that paraplegin mutations lead to mitochondrial DNA deletions by impairing proteins involved in the homeostasis of the mitochondrial genome. These studies increase our understanding of the molecular pathogenesis of SPG7 mutations and suggest that SPG7 testing should be included in the diagnostic workup of autosomal recessive, progressive external ophthalmoplegia, especially if spasticity is present.

• Belengeanu, Valerica; Gamage, Thilini Yaddehi; Farcas, Sorina; Stoian, Monica; Andreescu, Nicoleta & Belengeanu, Alina [Show all 8 contributors for this article] (2014). A de novo 2.3Mb deletion in 2q24.2q24.3 in a 20-month-old developmentally delayed girl. Gene. ISSN 0378-1119. 539(1), p. 168–172. doi: 10.1016/j.gene.2014.01.060. Full text in Research Archive
• Misceo, Doriana; Holmgren, Asbjørn; Louch, William Edward; Holme, Pål Andre; Mizobuchi, Masahiro & Morales, Raul J. [Show all 14 contributors for this article] (2014). A Dominant STIM1 Mutation Causes Stormorken Syndrome. Human Mutation. ISSN 1059-7794. 35(5), p. 556–564. doi: 10.1002/humu.22544. Full text in Research Archive
• Vetvik, Katja K; Sonerud, Tonje; Lindeberg, Mona Mari; Luders, Torben; Størkson, Ragnhild Helene & Jonsdottir, Kristin [Show all 9 contributors for this article] (2014). Globular adiponectin and its downstream target genes are up-regulated locally in human colorectal tumors: Ex vivo and in vitro studies. Metabolism: Clinical and Experimental. ISSN 0026-0495. 63(5), p. 672–681. doi: 10.1016/j.metabol.2014.02.001. Full text in Research Archive
• Askautrud, Hanne Arenberg; Gjernes, Elisabet; Gunnes, Gjermund; Sletten, Marit; Ross, D. T. & Børresen-Dale, Anne-Lise [Show all 9 contributors for this article] (2014). Global Gene Expression Analysis Reveals a Link between NDRG1 and Vesicle Transport. PLOS ONE. 9(1). doi: 10.1371/journal.pone.0087268. Full text in Research Archive Show summary

  N-myc downstream-regulated gene 1 (NDRG1) is induced by cellular stress such as hypoxia and DNA damage, and in humans, germ line mutations cause Charcot-Marie-Tooth disease. However, the cellular roles of NDRG1 are not fully understood. Previously, NDRG1 was shown to mediate doxorubicin resistance under hypoxia, suggesting a role for NDRG1 in cell survival under these conditions. We found decreased apoptosis in doxorubicin-treated cells expressing NDRG1 shRNAs under normoxia, demonstrating a requirement for NDRG1 in apoptosis in breast epithelial cells under normal oxygen pressure. Also, different cellular stress regimens, such as hypoxia and doxorubicin treatment, induced NDRG1 through different stress signalling pathways. We further compared expression profiles in human breast epithelial cells ectopically over-expressing NDRG1 with cells expressing NDRG1 shRNAs in order to identify biological pathways where NDRG1 is involved. The results suggest that NDRG1 may have roles connected to vesicle transport.

• Jesuthasan, Christeen Ramane Pedurupillay; Misceo, Doriana; Gamage, Thilini Yaddehi; Dissanayake, Vajira H.W & Frengen, Eirik (2014). Post-zygotic breakage of a dicentric chromosome results in mosaicism for a telocentric 9p marker chromosome in a boy with developmental delay. Gene. ISSN 0378-1119. 533(1), p. 403–410. doi: 10.1016/j.gene.2013.09.090. Full text in Research Archive
• Helle, Johan Robert; Barøy, Tuva; Misceo, Doriana; Braaten, Øivind; Fannemel, Madeleine & Frengen, Eirik (2013). Hyperphagia, Mild Developmental Delay But Apparently No Structural Brain Anomalies in a Boy Without SOX3 Expression. American Journal of Medical Genetics. Part A. ISSN 1552-4825. 161A(5), p. 1137–1142. doi: 10.1002/ajmg.a.35823. Full text in Research Archive
• Barøy, Tuva; Misceo, Doriana; Strømme, Petter; Stray-Pedersen, Asbjørg; Holmgren, Asbjørn & Rødningen, Olaug Kristin [Show all 12 contributors for this article] (2013). Haploinsufficiency of two histone modifier genes on 6p22.3, ATXN1 and JARID2, is associated with intellectual disability. Orphanet Journal of Rare Diseases. 8. doi: 10.1186/1750-1172-8-3. Full text in Research Archive
• Gamage, Thilini Yaddehi; Misceo, Doriana; Fannemel, Madeleine & Frengen, Eirik (2013). A balanced de novo inv(7)(p14.3q22.3) disrupting PDE1C and ATXN7L1 in a 14-year old developmentally delayed boy. European Journal of Medical Genetics. ISSN 1769-7212. 56(7), p. 361–364. doi: 10.1016/j.ejmg.2013.04.005. Full text in Research Archive
• Misceo, Doriana; Barøy, Tuva; Helle, Johan Robert; Braaten, Øivind; Fannemel, Madeleine & Frengen, Eirik (2012). 1.5 Mb deletion of chromosome 4p16.3 associated with postnatal growth delay, psychomotor impairment, epilepsy, impulsive behavior and asynchronous skeletal development. Gene. ISSN 0378-1119. 507(1), p. 85–91. doi: 10.1016/j.gene.2012.07.021. Full text in Research Archive
• Nakasone, Elizabeth S.; Askautrud, Hanne Arenberg; Kees, Tim; Park, Jae-Hyun; Plaks, Vicki & Ewald, Andrew J. [Show all 16 contributors for this article] (2012). Imaging Tumor-Stroma Interactions during Chemotherapy Reveals Contributions of the Microenvironment to Resistance. Cancer Cell. ISSN 1535-6108. 21(4), p. 488–503. doi: 10.1016/j.ccr.2012.02.017. Full text in Research Archive
• Floor, Karyn; Barøy, Tuva; Misceo, Doriana; Kanavin, Øivind J.; Fannemel, Madeleine & Frengen, Eirik (2012). A 1 Mb de novo deletion within 11q13.1q13.2 in a boy with mild intellectual disability and minor dysmorphic features. European Journal of Medical Genetics. ISSN 1769-7212. 55(12), p. 695–699. doi: 10.1016/j.ejmg.2012.08.002. Full text in Research Archive
• Misceo, Doriana; Rødningen, Olaug Kristin; Barøy, Tuva; Sorte, Hanne Sørmo; Mellembakken, Jan Roar & Strømme, Petter [Show all 8 contributors for this article] (2011). A Translocation Between Xq21.33 and 22q13.33 Causes an Intragenic SHANK3 Deletion in a Woman With Phelan-McDermid Syndrome and Hypergonadotropic Hypogonadism. American Journal of Medical Genetics. ISSN 0148-7299. 155(2), p. 403–408. doi: 10.1002/ajmg.a.33798. Full text in Research Archive
• Barøy, Tuva; Misceo, Doriana; Braaten, Øivind; Helle, Johan Robert; Fannemel, Madeleine & Strømme, Petter [Show all 7 contributors for this article] (2010). A de novo 15q13.2q13.3 deletion in a boy with an Angelman syndrome like phenotype. European Journal of Medical Genetics. ISSN 1769-7212. 53(4), p. 221–224. doi: 10.1016/j.ejmg.2010.03.010. Full text in Research Archive
• Barøy, Tuva; Sørensen, Kirsten; Lindeberg, Mona Mari & Frengen, Eirik (2010). shRNA Expression Constructs Designed Directly from siRNA Oligonucleotide Sequences. Molecular Biotechnology. ISSN 1073-6085. 45(2), p. 116–120. doi: 10.1007/s12033-010-9247-8. Full text in Research Archive
• Shaposhnikov, Sergey; Frengen, Eirik & Collins, Andrew Richard (2009). Increasing the resolution of the comet assay using fluorescent in situ hybridization-a review. Mutagenesis. ISSN 0267-8357. 24(5), p. 383–389. doi: 10.1093/mutage/gep021. Full text in Research Archive
• Skinningsrud, Beate; Husebye, Einar; Husebye, Eystein Sverre; Gilfillan, Gregor D; Frengen, Eirik & Erichsen, Aage [Show all 13 contributors for this article] (2009). X-Linked Congenital Adrenal Hypoplasia with Hypogonadotropic Hypogonadism Caused by an Inversion Disrupting a Conserved Noncoding Element Upstream of the NR0B1 (DAX1) Gene. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 94(10), p. 4086–4093. doi: 10.1210/jc.2009-0923. Full text in Research Archive
• Chandriani, S; Frengen, Eirik; Cowling, V; Pendergrass, SA; Perou, CM & Whitfield, ML [Show all 7 contributors for this article] (2009). A Core MYC Gene Expression Signature is prominent in basal-like breast cancer but only partially overlaps the Core Serum Response. PLOS ONE. 4(8), p. 6693–6693. doi: 10.1371/journal.pone.0006693. Full text in Research Archive Show summary

  Background The MYC oncogene contributes to induction and growth of many cancers but the full spectrum of the MYC transcriptional response remains unclear. Methodology/Principal Findings Using microarrays, we conducted a detailed kinetic study of genes that respond to MYCN or MYCNΔMBII induction in primary human fibroblasts. In parallel, we determined the response to steady state overexpression of MYCN and MYCNΔMBII in the same cell type. An overlapping set of 398 genes from the two protocols was designated a ‘Core MYC Signature’ and used for further analysis. Comparison of the Core MYC Signature to a published study of the genes induced by serum stimulation revealed that only 7.4% of the Core MYC Signature genes are in the Core Serum Response and display similar expression changes to both MYC and serum. Furthermore, more than 50% of the Core MYC Signature genes were not influenced by serum stimulation. In contrast, comparison to a panel of breast cancers revealed a strong concordance in gene expression between the Core MYC Signature and the basal-like breast tumor subtype, which is a subtype with poor prognosis. This concordance was supported by the higher average level of MYC expression in the same tumor samples. Conclusions/Significance The Core MYC Signature has clinical relevance as this profile can be used to deduce an underlying genetic program that is likely to contribute to a clinical phenotype. Therefore, the presence of the Core MYC Signature may predict clinical responsiveness to therapeutics that are designed to disrupt MYC-mediated phenotypes. © 2009 Chandriani et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

• Askautrud, Hanne A; Størvold, G; Lindeberg, Mona M; Thorsen, Jim; Prydz, Hans & Frengen, Eirik (2009). Regulated expression of a transgene introduced on an oriP/EBNA-1 PAC shuttle vector into human cells. BMC Biotechnology. 9. doi: 10.1186/1472-6750-9-88. Full text in Research Archive Show summary

  Background Sequencing of the human genome has led to most genes being available in BAC or PAC vectors. However, limited functional information has been assigned to most of these genes. Techniques for the manipulation and transfer of complete functional units on large DNA fragments into human cells are crucial for the analysis of complete genes in their natural genomic context. One limitation of the functional studies using these vectors is the low transfection frequency. Results We have constructed a shuttle vector, pPAC7, which contains both the EBNA-1 gene and oriP from the Epstein-Barr virus allowing stable maintenance of PAC clones in the nucleus of human cells. The pPAC7 vector also contains the EGFP reporter gene, which allows direct monitoring of the presence of PAC constructs in transfected cells, and the Bsr-cassette that allows highly efficient and rapid selection in mammalian cells by use of blasticidin. Positive selection for recombinant PAC clones is obtained in pPAC7 because the cloning sites are located within the SacBII gene. We show regulated expression of the CDH3 gene carried as a 132 kb genomic insert cloned into pPAC7, demonstrating that the pPAC7 vector can be used for functional studies of genes in their natural genomic context. Furthermore, the results from the transfection of a range of pPAC7 based constructs into two human cell lines suggest that the transfection efficiencies are not only dependent on construct size. Conclusion The shuttle vector pPAC7 can be used to transfer large genomic constructs into human cells. The genes transferred could potentially contain all long-range regulatory elements, including their endogenous regulatory promoters. Introduction of complete genes in PACs into human cells would potentially allow complementation assays to identify or verify the function of genes affecting cellular phenotypes.

• Misceo, Doriana; Rocchi, M; Hagen, Carl Birger van der & Frengen, Eirik (2009). A Partial Trisomy 1q Patient With a Deletion 1q22 and an Insertion 1(q42q44) Into 1q22. American Journal of Medical Genetics. ISSN 0148-7299. 149A(2), p. 290–293. doi: 10.1002/ajmg.a.32623. Full text in Research Archive
• Misceo, Doriana; Fannemel, Madeleine; Barøy, Tuva; Roberto, Roberta; Tvedt, B & Jaeger, T [Show all 9 contributors for this article] (2009). SCA27 caused by a chromosome translocation: further delineation of the phenotype. Neurogenetics. ISSN 1364-6745. 10(4), p. 371–374. doi: 10.1007/s10048-009-0197-x. Full text in Research Archive
• Askautrud, Hanne Arenberg; Gjernes, Elisabet; Størvold, Gro Leite; Lindeberg, Mona Mari; Thorsen, J & Prydz, Hans Peter B [Show all 7 contributors for this article] (2009). Regulated expression of a transgene introduced on an oriP/EBNA-1 PAC shuttle vector into human cells. BMC Biotechnology. 9. doi: 10.1186/1472-6750-9-88. Full text in Research Archive
• Misceo, Doriana; Ørstavik, Karen Helene; Lybæk, H; Sandvig, I; Ormerod, E & Houge, G [Show all 7 contributors for this article] (2009). Inheritance of a terminal 7.1 Mb 18p deletion flanked by a 2.3 Mb duplication from a physically normal mother. American Journal of Medical Genetics. ISSN 0148-7299. 149A(12), p. 2877–2881. doi: 10.1002/ajmg.a.33106. Full text in Research Archive
• Stavik, Benedicte; Skretting, Grethe; Sletten, Marit; Frengen, Eirik; Sandset, Per Morten & Iversen, Nina (2009). Knockdown of TFPI expression in Sum102 breast cancer cells leads to pro-angiogenic phenotypes. Journal of Thrombosis and Haemostasis. ISSN 1538-7933. 7. Full text in Research Archive
• Barøy, Tuva; Misceo, Doriana & Frengen, Eirik (2008). Strukturell variasjon i genomet bidrar til variasjon i egenskaper. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 128(17), p. 1951–1955. Full text in Research Archive
• Shaposhnikov, Sergey; Akopov, SB; Chernov, IP; Thomsen, PD; Joergensen, C & Collins, Andrew Richard [Show all 8 contributors for this article] (2007). A map of nuclear matrix attachment regions within the breast cancer loss-of-heterozygosity region on human chromosome 16q22.1. Genomics. ISSN 0888-7543. 89, p. 354–361. doi: 10.1016/j.ygeno.2006.11.003. Full text in Research Archive
• Størvold, Gro Leite; Gjernes, Elisabet; Askautrud, Hanne Arenberg; Børresen-Dale, Anne-Lise; Perou, Charles M & Frengen, Eirik (2007). A retroviral vector for siRNA expression in mammalian cells. Molecular Biotechnology. ISSN 1073-6085. 35(3), p. 275–282. Full text in Research Archive
• Størvold, GL; Andersen, TI; Perou, CM & Frengen, Eirik (2006). siRNA, a potential tool for future breast cancer therapy? Critical reviews in oncogenesis. ISSN 0893-9675. 12, p. 127–150. Full text in Research Archive
• Thorsen, Jim; Zhu, B.P; Frengen, Eirik; Osoegawa, Kazutoyo; Jong, Pieter J. de & Koop, Ben F. [Show all 8 contributors for this article] (2005). A highly redundant BAC library of Atlantic salmon (Salmo salar): an important tool for salmon projects. BMC Genomics. 6, p. 50–50. Full text in Research Archive Show summary

  Conclusion: Identification of genes and genomic regions of interest is greatly aided by the availability of the CHORI-214 Atlantic salmon BAC library. We have demonstrated the library's ability to identify specific genes and genetic markers using hybridization, PCR and fingerprinting experiments. In addition, multiple fingerprinting contigs indicated a pseudo-tetraploidity of the Atlantic salmon genome. The highly redundant CHORI-214 BAC library is expected to be an important resource for mapping and sequencing of the Atlantic salmon genome.

• Thorsen, J; Zhu, BL; Frengen, Eirik; Osoegawa, K; Jong, PJ de & Koop, BF [Show all 8 contributors for this article] (2005). A highly redundant BAC library of Atlantic salmon (Salmo salar): an important tool for salmon projects. BMC Genomics. 6. Full text in Research Archive

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• Sumathipala, Dulika Sanjeewani; Strømme, Petter; Gilissen, Christian; Corominas, Jordi; Frengen, Eirik & Misceo, Doriana (2019). TBCK encephaloneuropathy with abnormal lysosomal storage: Use of a structural variant bioinformatics pipeline on whole-genome sequencing data unravels a 20-year-old clinical mystery. Pediatric Neurology. ISSN 0887-8994. 96, p. 74–75. doi: 10.1016/j.pediatrneurol.2019.02.001. Full text in Research Archive
• Barøy, Tuva; Misceo, Doriana; Fannemel, Madeleine; Stormyr, Alice; Rødningen, Olaug Kristin & Helle, Johan Robert [Show all 12 contributors for this article] (2010). Two girls with mental retardation and behavioural abnormalities: Is the deletion of the ATXN1 gene on 6p22.3 a major factor in causing the phenotype? Full text in Research Archive
• Misceo, Doriana; BJØRGO, KATHRINE; Ormerod, Eli; RINGEN, ØYVIND; Rocchi, Mariano & Hagen, Carl Birger van der [Show all 7 contributors for this article] (2008). A de novo 6p interstitial deletion and a complex translocation involving chromosomes 2, 6, and 14 in a mildly developmentally delayed patient. American Journal of Medical Genetics. Part A. ISSN 1552-4825. 146A(24), p. 3230–3233. doi: 10.1002/ajmg.a.32582. Full text in Research Archive
• Ørstavik, Karen Helene; Misceo, Doriana; Lybæk, H; Frengen, Eirik & Houge, G (2008). A terminal 7,1 Mb chromosome 18p deletion flanked by a 2,3 Mb duplication in a phenotypically normal mother and her microcephalic and mentally retarded son. European Journal of Human Genetics. ISSN 1018-4813. 16. Full text in Research Archive
• Misceo, Doriana; BJØRGO, KATHRINE; Ormerod, E; RINGEN, ØYVIND; Rocchi, M & Hagen, Carl Birger van der [Show all 7 contributors for this article] (2008). A patient with a 6p interstital deletion and a de novo complex translocation involving chromosomes 2, 6 and 14. European Journal of Human Genetics. ISSN 1018-4813. 16. Full text in Research Archive
• Stavik, Benedicte; Skretting, Grethe; Sletten, Marit; Frengen, Eirik; Sandset, Per Morten & Iversen, Nina (2008). Stable knockdown of TFPI in cancer cells influences genes involved in angiogenesis. Full text in Research Archive
• Shaposhnikov, Sergey; Akopov, S; Chernov, I I.; Nikolaev, LG; Frengen, Eirik & Collins, Andrew Richard [Show all 7 contributors for this article] (2007). A map of nuclear matrix attachment regions within the breast cancer loss-of-heterozygosity region on human chromosome 16q22.1. Full text in Research Archive
• Askautrud, Hanne Arenberg; Gjernes, Elisabet; Størvold, Gro Leite; Børresen-Dale, Anne-Lise & Frengen, Eirik (2006). Hypoxia response in breast cancer models. Mechanisms and Models of Cancer. Full text in Research Archive
• Gjernes, Elisabet; Størvold, Gro Leite; Askautrud, Hanne Arenberg; Børresen-Dale, Anne-Lise; Perou, Charles M & Frengen, Eirik (2005). Functional characterization of genes involved in the development of breast cancer. Full text in Research Archive
• Driouch, K; Prydz, Hans Peter B; Lidereau, R & Frengen, Eirik (2003). Altered expression of the candidate tumor suppressor gene, WWOX, in human breast tumors. European Journal of Human Genetics. ISSN 1018-4813. 10, p. 86–86. Full text in Research Archive
• Shaposhnikov, Sergey; Frengen, Eirik; Thomsen, P; Zverev, V & Prydz, Hans Peter B (2003). Investigation of chromosomal DNA loop organization within a region of human chromosome 16q22.1. European Journal of Human Genetics. ISSN 1018-4813. 10, p. 170–170. Full text in Research Archive

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