157 results on '"Hoffjan S"'
Search Results
2. Association of TNFAIP3 and TNFRSF1A variation with multiple sclerosis in a German case–control cohort
- Author
-
Hoffjan, S., Okur, A., Epplen, J. T., Wieczorek, S., Chan, A., and Akkad, D. A.
- Published
- 2015
- Full Text
- View/download PDF
3. New cases of adult-onset Sandhoff disease with a cerebellar or lower motor neuron phenotype
- Author
-
Delnooz, C.C.S., Lefeber, D.J., Langemeijer, S.M.C., Hoffjan, S., Dekomien, G., Zwarts, M.J., Van Engelen, B.G., Wevers, R.A., Schelhaas, H.J., and van de Warrenburg, B.P.C.
- Subjects
Sandhoff disease -- Diagnosis ,Sandhoff disease -- Development and progression ,Sandhoff disease -- Care and treatment ,Sandhoff disease -- Case studies ,Cerebellar ataxia -- Case studies ,Health ,Psychology and mental health - Published
- 2010
4. Novel association of the CD226 (DNAM-1) Gly307Ser polymorphism in Wegener's granulomatosis and confirmation for multiple sclerosis in German patients
- Author
-
Wieczorek, S, Hoffjan, S, Chan, A, Rey, L, Harper, L, Fricke, H, Holle, J U, Gross, W L, Epplen, J T, and Lamprecht, P
- Published
- 2009
- Full Text
- View/download PDF
5. Asthma genetics 2006: the long and winding road to gene discovery
- Author
-
Ober, C and Hoffjan, S
- Published
- 2006
- Full Text
- View/download PDF
6. Association of interleukin-8 receptor α polymorphisms with chronic obstructive pulmonary disease and asthma
- Author
-
Stemmler, S, Arinir, U, Klein, W, Rohde, G, Hoffjan, S, Wirkus, N, Reinitz-Rademacher, K, Bufe, A, Schultze-Werninghaus, G, and Epplen, J T
- Published
- 2005
- Full Text
- View/download PDF
7. Effect of Recombinant Human DNase on α1-Proteinase Inhibitor Function: An Experimental Approach to the Combined Clinical Use of rhDNase and α1-PI in CF Patients
- Author
-
Hansen, G., Hoffjan, S., Mosler, K., and Schuster, A.
- Published
- 2001
- Full Text
- View/download PDF
8. Ring chromosome 22 and neurofibromatosis type II: proof of two-hit model for the loss of the NF2 gene in the development of meningioma
- Author
-
Zirn, B, Arning, L, Bartels, I, Shoukier, M, Hoffjan, S, Neubauer, B, and Hahn, A
- Published
- 2012
- Full Text
- View/download PDF
9. Variation in genes of the epidermal differentiation complex in German atopic dermatitis patients
- Author
-
Stemmler, S., Nothnagel, M., Parwez, Q., Petrasch-Parwez, E., Epplen, J. T., and Hoffjan, S.
- Published
- 2009
- Full Text
- View/download PDF
10. On the role of the epidermal differentiation complex in ichthyosis vulgaris, atopic dermatitis and psoriasis
- Author
-
Hoffjan, S. and Stemmler, S.
- Published
- 2007
11. A case of sporadic Bazex–Dupré–Christol syndrome presenting with scarring folliculitis of the scalp
- Author
-
GAMBICHLER, T., HOFFJAN, S., ALTMEYER, P., and BECHARA, F. G.
- Published
- 2007
12. Association screen for atopic dermatitis candidate gene regions using microsatellite markers in pooled DNA samples
- Author
-
Hoffjan, S., Parwez, Q., Petrasch-Parwez, E., Falkenstein, D., Nothnagel, M., and Epplen, J. T.
- Published
- 2006
13. Severe respiratory syncytial virus infections and reduced interferon-γ generation in vitro
- Author
-
SCHAUER, U., HOFFJAN, S., ROTHOEFT, T., BARTZ, H., KÖNIG, S., FUCHS, E., BITTSCHEIDT, J., KÖCHLING, A., and STEPHAN, V.
- Published
- 2004
14. Respiratory syncytial virus decreases the capacity of myeloid dendritic cells to induce interferon-γ in naïve T cells
- Author
-
BARTZ, H., TÜRKEL, Ö., HOFFJAN, S., ROTHOEFT, T., GONSCHOREK, A., and SCHAUER, U.
- Published
- 2003
15. Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS.
- Author
-
Schrewe, L., Lill, C. M., T. Liu, Salmen, A., Gerdes, L. A., Guillot-Noel, L., Akkad, D. A., Blaschke, P., Graetz, C., Hoffjan, S., Kroner, A., Demir, S., Böhme, A., Rieckmann, P., El Ali, A., Hagemann, N., Hermann, D. M., Cournu-Rebeix, I., Zipp, F., and Kümpfel, T.
- Subjects
MULTIDRUG resistance ,IMMUNOREGULATION ,APOLIPOPROTEIN E ,ENCEPHALOMYELITIS ,MULTIPLE sclerosis ,ANIMAL experimentation ,ANIMALS ,APOLIPOPROTEINS ,DEMYELINATION ,FLUORESCENT antibody technique ,MICE ,POLYMERASE chain reaction ,SEX distribution ,GENOTYPES - Abstract
Background: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS.Methods: MOG(35-55) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses.Results: EAE disease course was slightly attenuated in male apoE-deficient (apoE (-/-) ) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE (-/-) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex.Conclusions: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
16. Association of TNFAIP3 and TNFRSF1 A variation with multiple sclerosis in a German case-control cohort.
- Author
-
Hoffjan, S., Okur, A., Epplen, J. T., Wieczorek, S., Chan, A., and Akkad, D. A.
- Subjects
- *
MULTIPLE sclerosis , *TUMOR necrosis factors , *AUTOIMMUNE diseases , *CASE-control method , *GENETIC polymorphisms - Abstract
Variations in two genes of the tumour necrosis factor ( TNF) alpha pathway have been implicated in the pathogenesis of autoimmune diseases: polymorphisms in the TNFRSF1A gene, encoding TNF receptor 1, showed significant association with MS in genomewide association scans, and variation in or near the TNFAIP3 gene, coding for a negative regulator of NFkB, was associated with MS, systemic lupus erythematosus, diabetes and rheumatoid arthritis. This study aimed at investigating association of MS with variation in the TNFRSF1A gene as well as in the TNFAIP3 gene region in an independent German case-control cohort. Four hundred and ninety-seven unrelated patients with MS and 878 healthy controls were genotyped with restriction enzyme digestion or TaqMan assays for three polymorphisms in the TNFRSF1A gene and seven in the region of the TNFAIP3 gene. Allele, genotype and haplotype frequencies were compared between cases and controls by chi-square testing. We found significant association of rs10499194, located in the intergenic region upstream of TNFAIP3, with MS ( pc = 3.4 × 10−4). Further, the intronic SNP rs1800693 in TNFRSF1A showed moderate association ( pc = 0.033) with MS. In conclusion, evidence is accumulating that polymorphisms in both TNFAIP3 and TNFRSF1A genes play a role in MS pathogenesis. Additional studies are warranted to further elucidate the role of TNF pathway variation for MS development. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
17. Genetic Dissection of Marfan Syndrome and Related Connective Tissue Disorders: An Update 2012.
- Author
-
Hoffjan, S.
- Published
- 2012
- Full Text
- View/download PDF
18. Variation in the IL7RA and IL2RA genes in German multiple sclerosis patients
- Author
-
Akkad, D.A., Hoffjan, S., Petrasch-Parwez, E., Beygo, J., Gold, R., and Epplen, J.T.
- Subjects
- *
MULTIPLE sclerosis , *DEMYELINATION , *HEREDITY , *VIRUS diseases - Abstract
Abstract: Variation in the genes encoding the interleukin (IL) 7 and IL2 receptor α chains (IL7RA, IL2RA) was recently found associated with multiple sclerosis (MS). We evaluated the role of these two genes in a large German MS case–control cohort. Five single nucleotide polymorphisms (SNPs) in IL7RA and four in IL2RA were genotyped in 1319 MS patients and 908 controls by means of restriction enzyme digestion or TaqMan assays and subsequently evaluated for association with MS. IL7RA expression was measured via quantitative real time PCR in 24 subjects. We replicated the association of exon 6 variation (rs6897932) in IL7RA with MS. Yet, this association was only found in patients with primary progressive (pp) or secondary progressive (sp) disease course (p =0.0004). Expression analysis did not show differences in IL7RA expression depending on genotypes at this locus, while reduced expression of the soluble receptor was observed in patients with pp and sp MS irrespective of genotype. In the IL2RA gene, significant associations of SNPs in introns 3 and 7 with MS subtypes were obvious. Together these results confirm involvement of polymorphisms in the IL7RA and IL2RA genes in MS pathogenesis and suggest that IL7RA variation may primarily affect chronic disease courses. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
19. Zur Genetik der chronisch-obstruktiven Lungenerkrankung.
- Author
-
Arinir, U., Hoffjan, S., Knoop, H., Schultze-Werninghaus, G., Epplen, J. T., and Rohde, G.
- Published
- 2009
- Full Text
- View/download PDF
20. Association of interleukin-8 receptorapolymorphisms with chronic obstructive pulmonary disease and asthma.
- Author
-
Stemmler, S., Arinir, U., Klein, W., Rohde, G., Hoffjan, S., Wirkus, N., Reinitz-Rademacher, K., Bufe, A., Schultze-Werninghaus, G., and Epplen, J. T.
- Subjects
OBSTRUCTIVE lung diseases ,LUNG diseases ,RESPIRATORY obstructions ,ASTHMA ,ASTHMATICS ,GENETIC mutation - Abstract
Chronic obstructive pulmonary disease (COPD) and asthma are common complex diseases characterized by airflow obstruction and inflammatory processes in the small airways. lnterleukin 8 (IL-8) is a potent proinflammatory cytokine which interacts with the IL-8 receptora(IL8RA, CXCR1) andß(IL8RB, CXCR2), leading to activation and migration of leukocytes. In order to evaluate the role of the IL8RA gene in the pathogenesis of COPD and asthma, we screened the coding region of IL8RA for mutations by means of single-strand conformation polymorphism analysis in 50 COPD patients and identified three exchanges (M31R, S276T and R335C). These three polymorphisms were subsequently genotyped in 182 adult patients with COPD, 68 adult patients and 130 children with asthma as well as 454 healthy controls. The frequencies of the IL8RA 31R and 335C alleles were significantly increased in patients with COPD and in children with asthma compared to healthy controls (P=0.0073 and 0.023, respectively). Thus, these polymorphisms may play a role in the pathogenesis of COPD and asthma.Genes and Immunity (2005) 6, 225-230. doi:10.1038/sj.gene.6364181 Published online 17 March 2004 [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
21. Severe respiratory syncytial virus infections and reduced interferon-γ generationin vitro.
- Author
-
Schauer, U., Hoffjan, S., Rothoeft, T., Bartz, H., König, S., Fuchs, E., Bittscheidt, J., Köchling, A., and Stephan, V.
- Subjects
- *
RESPIRATORY syncytial virus , *ANTINEOPLASTIC agents , *IMMUNE response , *TOXIC shock syndrome , *LYMPHOID tissue , *ANTIVIRAL agents - Abstract
To study the consequences of the interaction of respiratory syncytial virus (RSV) with dendritic cellsin vitro, we established a model of the primary immune response using dendritic cells, autologous naive T cells and the superantigen toxic shock syndrome toxin 1 (TSST 1). About 10% of the naive T cells express the T cell receptor chain Vβ2. These cells were stimulated by TSST 1 and could be analysed by flow cytometry. Cultures infected with RSV produced significantly less interferon-γ compared to uninfected cultures. In a first set of experiments we evaluated whether this culture model using isolated CD4+ CD45RA+ T cells, in fact, reflects the primary immune response. In a prospective study, cells were isolated from 13 children at birth, at 1 year of age and at 4 years of age. RSV reduced interferon-γ production at all the age groups analysed and the results were stable over time within a given individual. In a second set of experiments, we asked whether clinical differences in the course of RSV infection are due to variations in the cellular immune response. At the age of 1 year (5–9 months after the RSV epidemic) dendritic cells and naive T cells were obtained from 27 children with a history of bronchiolitis, from 15 children with a benign course of RSV infection and from 26 controls without RSV infection. The frequency of interferon-γ-producing cells in RSV infected cultures was significantly lower (P < 0·001) in cultures from children with a history of RSV bronchiolitis compared to children with mild RSV infection. Cultures from children without infection displayed a wide range of results. Overall, interferon-γ generation in this group was still lower (P < 0·05) than in the group with mild RSV infection. Because we have ruled out that memory cells play a role in the experiments performed, the most likely explanation for our results is that a high generation of interferon-γ in the primary immune response protects from severe RSV mediated disease. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
22. Effect of Recombinant Human DNase on a1-Proteinase Inhibitor Function: An Experimental Approach to the Combined Clinical Use of rhDNase and a1-PI in CF Patients.
- Author
-
Hansen, G., Hoffjan, S., Mosler, K., and Schuster, A.
- Subjects
RECOMBINANT DNA ,PROTEINASES ,CHEMICAL inhibitors - Abstract
Chronic inflammation in cystic fibrosis (CF) airways leads to high concentrations of deoxyribonucleic acid (DNA) and neutrophil elastase (NE). Both play a major role in CF lung pathophysiology and are aims of new therapeutic approaches: rhDNase degrades highly viscosic DNA and a1-proteinase inhibitor (a1-PI) inhibits NE activity and thereby pulmonary inflammation and hypersecretion. Given the reports on increased sputum NE concentrations upon rhDNase inhalation, there is a rationale for a combined rhDNase/a1-PI treatment. With the question of whether a combined therapy is feasible, we first investigated in vitro whether incubation of CF sputum with rhDNase changes proteolytic and secretagogue activity of sputum supernatants and its inhibition by a1-PI. Next, we studied whether incubation of a1-PI with rhDNase impairs the inhibitory effect of a1-PI on proteolytic activity of NE and the inhibitory effect of a1-PI on NE-induced secretion from a human mucoepidermoid cell line. Incubation of CF sputum with rhDNase led to a twofold increase in sputum NE activity. Correspondingly, the inhibitory effect of a1-PI on sputum NE activity and on secretion induced by these sputum samples was significantly reduced by rhDNase. Preincubation of a1-PI with rhDNase significantly reduced the inhibitory effect of a1-PI on purified NE activity and on NE-induced secretion. However, this effect was limited to a1-PI concentrations lower than those achievable after inhalation. Therefore, impairment of a1-PI function by rhDNase is not likely to be relevant in vivo, provided that a sufficient dosage of a1-PI is inhaled. [ABSTRACT FROM AUTHOR]
- Published
- 2001
- Full Text
- View/download PDF
23. Analysis of variation in the IL7RA and IL2RA genes in atopic dermatitis
- Author
-
Hoffjan, S., Beygo, J., Akkad, D.A., Parwez, Q., Petrasch-Parwez, E., and Epplen, J.T.
- Published
- 2009
- Full Text
- View/download PDF
24. Time-dependent Effects of Dog Exposure and Genotype at Immune-Related Genes on Wheezing and Atopy in Early Childhood
- Author
-
Bufford, J., Li, Z., Reardon, C., Roberg, K.A., Tisler, C., Anderson, E., DaSilva, D., Ostrovnaja, I., Hoffjan, S., Nicolae, D., Gangnon, R., Ober, C., Lemanske, R.F., Jr., and Gern, J.E.
- Published
- 2006
- Full Text
- View/download PDF
25. Evaluation of the toll-like receptor 6 Ser249Pro polymorphism in patients with asthma, atopic dermatitis and chronic obstructive pulmonary disease
- Author
-
Reinitz-Rademacher Karin, Rohde Gernot, Arinir Umut, Petrasch-Parwez Elisabeth, Parwez Qumar, Stemmler Susanne, Hoffjan Sabine, Schultze-Werninghaus Gerhard, Bufe Albrecht, and Epplen Jörg T
- Subjects
Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background For allergic disorders, the increasing prevalence over the past decade has been attributed in part to the lack of microbial burden in developed countries ('hygiene hypothesis'). Variation in genes encoding toll-like receptors (TLRs) as the receptor system for the first innate immune response to microbial stimuli has been implicated in various inflammatory diseases. We evaluated here the role of a coding variation, Ser249Pro, in the TLR6 gene in the pathogenesis of asthma, atopic dermatitis (AD) and chronic obstructive pulmonary disease (COPD). Methods Genotyping of the Ser249Pro polymorphism in 68 unrelated adult patients and 132 unrelated children with asthma, 185 unrelated patients with COPD, 295 unrelated individuals with AD and 212 healthy control subjects was performed by restriction enzyme digestion. Results We found a weak association of the 249Ser allele with childhood asthma (p = 0.03). Yet, significance was lost after Bonferroni correction. No association was evident for AD or COPD. Conclusion Variation in TLR6 might play a role in the pathogenesis of childhood asthma.
- Published
- 2005
- Full Text
- View/download PDF
26. Association studies for asthma and atopic diseases: a comprehensive review of the literature
- Author
-
Nicolae Dan, Hoffjan Sabine, and Ober Carole
- Subjects
Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Hundreds of genetic association studies on asthma-related phenotypes have been conducted in different populations. To date, variants in 64 genes have been reported to be associated with asthma or related traits in at least one study. Of these, 33 associations were replicated in a second study, 9 associations were not replicated either in a second study or a second sample in the same study, and 22 associations were reported in just a single published study. These results suggest the potential for a great amount of heterogeneity underlying asthma. However, many of these studies are methodologically limited and their interpretation hampered by small sample sizes.
- Published
- 2003
- Full Text
- View/download PDF
27. Compound Heterozygous RYR1 Variants in a Patient with Severe Congenital Myopathy: Case Report and Comparison with Additional Cases of Recessive RYR1 -Related Myopathy.
- Author
-
Janßen S, Erbe LS, Kneifel M, Vorgerd M, Döring K, Lubieniecki KP, Lubieniecka JM, Gerding WM, Casadei N, Güttsches AK, Heyer C, Lücke T, Nguyen HHP, Köhler C, and Hoffjan S
- Subjects
- Child, Female, Humans, Male, Genes, Recessive, Genetic Association Studies, Muscular Diseases genetics, Mutation, Myotonia Congenita genetics, Pedigree, Phenotype, Heterozygote, Ryanodine Receptor Calcium Release Channel genetics
- Abstract
Pathogenic variants in the ryanodine receptor 1 ( RYR1 ) gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe forms usually showing recessive inheritance. However, genotype-phenotype correlations are complicated due to the large size of the gene and heterogeneous phenotypes. We present a 6-year-old patient with severe congenital myopathy, carrying a heterozygous pathogenic RYR1 variant inherited from the healthy mother. Through whole genome sequencing we identified a second, deep intronic RYR1 variant that has recently been described in another patient with severe congenital myopathy and shown to affect splicing. Segregation analyses confirmed the variants to be compound heterozygous. We compared our patient's phenotype to that of the patient from the literature as well as five additional patients with compound heterozygous RYR1 variants from our center. The main overlapping features comprised congenital onset, predominant muscular hypotonia, and normal creatine kinase (CK) levels, while overall clinical expression varied substantially. Interestingly, both patients carrying the new intronic splice variant showed a very severe disease course. More widespread use of genome sequencing will open the way for better genotype-phenotype correlations., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
- Published
- 2024
- Full Text
- View/download PDF
28. Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings.
- Author
-
Schmidt A, Danyel M, Grundmann K, Brunet T, Klinkhammer H, Hsieh TC, Engels H, Peters S, Knaus A, Moosa S, Averdunk L, Boschann F, Sczakiel HL, Schwartzmann S, Mensah MA, Pantel JT, Holtgrewe M, Bösch A, Weiß C, Weinhold N, Suter AA, Stoltenburg C, Neugebauer J, Kallinich T, Kaindl AM, Holzhauer S, Bührer C, Bufler P, Kornak U, Ott CE, Schülke M, Nguyen HHP, Hoffjan S, Grasemann C, Rothoeft T, Brinkmann F, Matar N, Sivalingam S, Perne C, Mangold E, Kreiss M, Cremer K, Betz RC, Mücke M, Grigull L, Klockgether T, Spier I, Heimbach A, Bender T, Brand F, Stieber C, Morawiec AM, Karakostas P, Schäfer VS, Bernsen S, Weydt P, Castro-Gomez S, Aziz A, Grobe-Einsler M, Kimmich O, Kobeleva X, Önder D, Lesmann H, Kumar S, Tacik P, Basin MA, Incardona P, Lee-Kirsch MA, Berner R, Schuetz C, Körholz J, Kretschmer T, Di Donato N, Schröck E, Heinen A, Reuner U, Hanßke AM, Kaiser FJ, Manka E, Munteanu M, Kuechler A, Cordula K, Hirtz R, Schlapakow E, Schlein C, Lisfeld J, Kubisch C, Herget T, Hempel M, Weiler-Normann C, Ullrich K, Schramm C, Rudolph C, Rillig F, Groffmann M, Muntau A, Tibelius A, Schwaibold EMC, Schaaf CP, Zawada M, Kaufmann L, Hinderhofer K, Okun PM, Kotzaeridou U, Hoffmann GF, Choukair D, Bettendorf M, Spielmann M, Ripke A, Pauly M, Münchau A, Lohmann K, Hüning I, Hanker B, Bäumer T, Herzog R, Hellenbroich Y, Westphal DS, Strom T, Kovacs R, Riedhammer KM, Mayerhanser K, Graf E, Brugger M, Hoefele J, Oexle K, Mirza-Schreiber N, Berutti R, Schatz U, Krenn M, Makowski C, Weigand H, Schröder S, Rohlfs M, Vill K, Hauck F, Borggraefe I, Müller-Felber W, Kurth I, Elbracht M, Knopp C, Begemann M, Kraft F, Lemke JR, Hentschel J, Platzer K, Strehlow V, Abou Jamra R, Kehrer M, Demidov G, Beck-Wödl S, Graessner H, Sturm M, Zeltner L, Schöls LJ, Magg J, Bevot A, Kehrer C, Kaiser N, Turro E, Horn D, Grüters-Kieslich A, Klein C, Mundlos S, Nöthen M, Riess O, Meitinger T, Krude H, Krawitz PM, Haack T, Ehmke N, and Wagner M
- Subjects
- Humans, Female, Male, Child, Germany, Exome Sequencing methods, Adolescent, Genetic Association Studies methods, Genetic Testing methods, Child, Preschool, Prospective Studies, Adult, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders diagnosis, Infant, Young Adult, Phenotype, High-Throughput Nucleotide Sequencing methods
- Abstract
Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
29. Optical Genome Mapping Reveals Disruption of the RASGRF2 Gene in a Patient with Developmental Delay Carrying a De Novo Balanced Reciprocal Translocation.
- Author
-
Lederbogen RC, Hoffjan S, Thiels C, Mau-Holzmann UA, Singer S, Yusenko MV, Nguyen HHP, and Gerding WM
- Subjects
- Humans, Male, ras Guanine Nucleotide Exchange Factors genetics, Chromosome Mapping, Chromosomes, Human, Pair 5 genetics, Intellectual Disability genetics, Intellectual Disability pathology, Translocation, Genetic, Developmental Disabilities genetics, Developmental Disabilities pathology
- Abstract
While balanced reciprocal translocations are relatively common, they often remain clinically silent unless they lead to the disruption of functional genes. In this study, we present the case of a boy exhibiting developmental delay and mild intellectual disability. Initial karyotyping revealed a translocation t(5;6)(q13;q23) between chromosomes 5 and 6 with limited resolution. Optical genome mapping (OGM) enabled a more precise depiction of the breakpoint regions involved in the reciprocal translocation. While the breakpoint region on chromosome 6 did not encompass any known gene, OGM revealed the disruption of the RASGRF2 (Ras protein-specific guanine nucleotide releasing factor 2) gene on chromosome 5, implicating RASGRF2 as a potential candidate gene contributing to the observed developmental delay in the patient. Variations in RASGRF2 have so far not been reported in developmental delay, but research on the RASGRF2 gene underscores its significance in various aspects of neurodevelopment, including synaptic plasticity, signaling pathways, and behavioral responses. This study highlights the utility of OGM in identifying breakpoint regions, providing possible insights into the understanding of neurodevelopmental disorders. It also helps affected individuals in gaining more knowledge about potential causes of their conditions.
- Published
- 2024
- Full Text
- View/download PDF
30. ACOX1 Gain-of-Function Variant in Two German Pediatric Patients, in One Case Mimicking Autoimmune Inflammatory Disease.
- Author
-
Thiels C, Lücke T, Rothoeft T, Lukas C, Nguyen HP, von Kleist-Retzow JC, Prokisch H, Grimmel M, Haack TB, and Hoffjan S
- Subjects
- Child, Humans, Myelin-Oligodendrocyte Glycoprotein, Vision Disorders, Autoimmune Diseases, Gain of Function Mutation
- Abstract
Mitchell syndrome is a very rare genetic disorder due to a specific de novo gain-of-function variant in acyl-CoA oxidase 1 ( ACOX1 ). So far, only five patients with this disease have been described worldwide. We present here two additional unrelated German patients found to carry the same heterozygous ACOX1 N237S variant through exome sequencing (ES). Both patients showed neurodegenerative clinical features starting from ∼4 to 5 years of age including progressive hearing loss, ataxia, ichthyosis, as well as progressive visual impairment leading to amaurosis, and died at the ages of 16 and 8 years, respectively. The first patient was clinically suspected to have anti-myelin oligodendrocyte glycoprotein-antibody-associated myelitis, but the disease course overall deteriorated despite extensive immunomodulatory therapy. The second patient was originally suspected to have a mitochondrial disorder due to intermittent elevated blood lactate. Since Mitchell syndrome has only been identified in 2020, the diagnosis in this second patient was only established through re-evaluation of ES data years after the original analysis. Comparison of all seven reported patients suggests that Mitchell syndrome often (but not always) clinically mimics autoimmune-inflammatory disease. Therefore, in patients with autoimmune central nervous system disease who do not respond adequately to standard therapies, re-evaluation of this diagnosis is needed and genetic analyses such as trio ES should be considered., Competing Interests: None declared., (Thieme. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
31. Canavan's spongiform leukodystrophy (Aspartoacylase deficiency) with emphasis on sonographic features in infancy: description of a case report and review of the literature.
- Author
-
Rossler L, Lemburg S, Weitkämper A, Thiels C, Hoffjan S, Nguyen HP, Lücke T, and Heyer CM
- Subjects
- Humans, Infant, Ultrasonography, Magnetic Resonance Imaging, Canavan Disease diagnostic imaging, Canavan Disease genetics, Bone Diseases
- Abstract
Canavan disease (CD; MIM 271,900) or spongy degeneration of the central nervous system (CNS) is a lethal, rare autosomal recessive leukodystrophy, first described in 1931 (Canavan in Arch Neurol Psychiatry 25: 299-308, 1931). The clinical presentation includes severe neurologic impairment and macrocephaly with onset of symptoms at the age of 3-5 months. Biochemical and genetic fundamentals of the disease are elucidated. Imaging diagnosis is principally based on MRI with important role of MR spectroscopy. We report the cerebral sonographic findings in a severely affected infant with CD: Diffuse hyperechogenicity and small multicystic changes of white matter as well as an inverted pattern of echogenicity between cortical gray and subcortical white matter. These findings are compared to to the few cases found in literature and to normal ultrasound examples. Finally, ultrasound and MRI imaging findings are correlated., (© 2022. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
32. Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the DMD Gene.
- Author
-
Erbe LS, Hoffjan S, Janßen S, Kneifel M, Krause K, Gerding WM, Döring K, Güttsches AK, Roos A, Buena Atienza E, Gross C, Lücke T, Nguyen HHP, Vorgerd M, and Köhler C
- Subjects
- Humans, Male, Chromosome Inversion, Chromosome Mapping, Dystrophin genetics, Exome Sequencing, Mutation, Muscular Dystrophy, Duchenne diagnosis, Muscular Dystrophy, Duchenne genetics
- Abstract
Duchenne muscular dystrophy (DMD) is a severe progressive muscle disease that mainly affects boys due to X-linked recessive inheritance. In most affected individuals, MLPA or sequencing-based techniques detect deletions, duplications, or point mutations in the dystrophin-encoding DMD gene. However, in a small subset of patients clinically diagnosed with DMD, the molecular cause is not identified with these routine methods. Evaluation of the 60 DMD patients in our center revealed three cases without a known genetic cause. DNA samples of these patients were analyzed using whole-exome sequencing (WES) and, if unconclusive, optical genome mapping (OGM). WES led to a diagnosis in two cases: one patient was found to carry a splice mutation in the DMD gene that had not been identified during previous Sanger sequencing. In the second patient, we detected two variants in the fukutin gene ( FKTN ) that were presumed to be disease-causing. In the third patient, WES was unremarkable, but OGM identified an inversion disrupting the DMD gene (~1.28 Mb) that was subsequently confirmed with long-read sequencing. These results highlight the importance of reanalyzing unsolved cases using WES and demonstrate that OGM is a useful method for identifying large structural variants in cases with unremarkable exome sequencing.
- Published
- 2023
- Full Text
- View/download PDF
33. A 21-year-old woman with progressive asymptomatic skin laxity in flexural regions.
- Author
-
Gambichler T, Hoffjan S, Nagel M, Terschlüsen M, Mansour R, Würfel L, Hoffmann K, Susok L, Dickel H, and Doerler M
- Subjects
- Female, Humans, Young Adult, Adult, Skin Aging
- Abstract
Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest.
- Published
- 2023
- Full Text
- View/download PDF
34. Microscopic and Biochemical Hallmarks of BICD2 -Associated Muscle Pathology toward the Evaluation of Novel Variants.
- Author
-
Unger A, Roos A, Gangfuß A, Hentschel A, Gläser D, Krause K, Doering K, Schara-Schmidt U, Hoffjan S, Vorgerd M, and Güttsches AK
- Subjects
- Humans, Biglycan metabolism, Proteomics, Mutation, Muscle, Skeletal metabolism, Microtubule-Associated Proteins metabolism, Muscular Atrophy, Spinal genetics
- Abstract
BICD2 variants have been linked to neurodegenerative disorders like spinal muscular atrophy with lower extremity predominance (SMALED2) or hereditary spastic paraplegia (HSP). Recently, mutations in BICD2 were implicated in myopathies. Here, we present one patient with a known and six patients with novel BICD2 missense variants, further characterizing the molecular landscape of this heterogenous neurological disorder. A total of seven patients were genotyped and phenotyped. Skeletal muscle biopsies were analyzed by histology, electron microscopy, and protein profiling to define pathological hallmarks and pathogenicity markers with consecutive validation using fluorescence microscopy. Clinical and MRI-features revealed a typical pattern of distal paresis of the lower extremities as characteristic features of a BICD2 -associated disorder. Histological evaluation showed myopathic features of varying severity including fiber size variation, lipofibromatosis, and fiber splittings. Proteomic analysis with subsequent fluorescence analysis revealed an altered abundance and localization of thrombospondin-4 and biglycan. Our combined clinical, histopathological, and proteomic approaches provide new insights into the pathophysiology of BICD2 -associated disorders, confirming a primary muscle cell vulnerability. In this context, biglycan and thrombospondin-4 have been identified, may serve as tissue pathogenicity markers, and might be linked to perturbed protein secretion based on an impaired vesicular transportation.
- Published
- 2023
- Full Text
- View/download PDF
35. Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome.
- Author
-
Ramond F, Dalgliesh C, Grimmel M, Wechsberg O, Vetro A, Guerrini R, FitzPatrick D, Poole RL, Lebrun M, Bayat A, Grasshoff U, Bertrand M, Witt D, Turnpenny PD, Faundes V, Santa María L, Mendoza Fuentes C, Mabe P, Hussain SA, Mullegama SV, Torti E, Oehl-Jaschkowitz B, Salmon LB, Orenstein N, Shahar NR, Hagari O, Bazak L, Hoffjan S, Prada CE, Haack T, and Elliott DJ
- Subjects
- Humans, Alternative Splicing, RNA-Binding Proteins genetics, HEK293 Cells, Protein Isoforms genetics, Serine-Arginine Splicing Factors genetics, Serine-Arginine Splicing Factors metabolism, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Autism Spectrum Disorder, Intellectual Disability genetics, Neurodevelopmental Disorders genetics
- Abstract
Purpose: Transformer2 proteins (Tra2α and Tra2β) control splicing patterns in human cells, and no human phenotypes have been associated with germline variants in these genes. The aim of this work was to associate germline variants in the TRA2B gene to a novel neurodevelopmental disorder., Methods: A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited. RNA sequencing and western blot analyses of Tra2β-1 and Tra2β-3 isoforms from patient-derived cells were performed. Tra2β1-GFP, Tra2β3-GFP and CHEK1 exon 3 plasmids were transfected into HEK-293 cells., Results: All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2β-3 isoform. All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature. Experimental studies showed that these variants decreased the expression of the canonical Tra2β-1 isoform, whereas they increased the expression of the Tra2β-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2β-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2β-1., Conclusion: Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein., Competing Interests: Conflict of Interest S.V.M. and E.T. are employees of GeneDx, LLC. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
36. Cas9-Mediated Nanopore Sequencing Enables Precise Characterization of Structural Variants in CCM Genes.
- Author
-
Skowronek D, Pilz RA, Bonde L, Schamuhn OJ, Feldmann JL, Hoffjan S, Much CD, Felbor U, and Rath M
- Subjects
- Humans, CRISPR-Cas Systems, Multiplex Polymerase Chain Reaction, Carrier Proteins genetics, Nanopore Sequencing, DNA Copy Number Variations
- Abstract
Deletions in the CCM1 , CCM2 , and CCM3 genes are a common cause of familial cerebral cavernous malformations (CCMs). In current molecular genetic laboratories, targeted next-generation sequencing or multiplex ligation-dependent probe amplification are mostly used to identify copy number variants (CNVs). However, both techniques are limited in their ability to specify the breakpoints of CNVs and identify complex structural variants (SVs). To overcome these constraints, we established a targeted Cas9-mediated nanopore sequencing approach for CNV detection with single nucleotide resolution. Using a MinION device, we achieved complete coverage for the CCM genes and determined the exact size of CNVs in positive controls. Long-read sequencing for a CCM1 and CCM2 CNV revealed that the adjacent ANKIB1 and NACAD genes were also partially or completely deleted. In addition, an interchromosomal insertion and an inversion in CCM2 were reliably re-identified by long-read sequencing. The refinement of CNV breakpoints by long-read sequencing enabled fast and inexpensive PCR-based variant confirmation, which is highly desirable to reduce costs in subsequent family analyses. In conclusion, Cas9-mediated nanopore sequencing is a cost-effective and flexible tool for molecular genetic diagnostics which can be easily adapted to various target regions.
- Published
- 2022
- Full Text
- View/download PDF
37. Homozygous Inversion on Chromosome 13 Involving SGCG Detected by Short Read Whole Genome Sequencing in a Patient Suffering from Limb-Girdle Muscular Dystrophy.
- Author
-
Pluta N, Hoffjan S, Zimmer F, Köhler C, Lücke T, Mohr J, Vorgerd M, Nguyen HHP, Atlan D, Wolf B, Zaum AK, and Rost S
- Subjects
- Humans, Female, Chromosomes, Human, Pair 13, Homozygote, Whole Genome Sequencing, Sarcoglycans genetics, Muscular Dystrophies, Limb-Girdle diagnosis, Muscular Dystrophies, Limb-Girdle genetics
- Abstract
New techniques in molecular genetic diagnostics now allow for accurate diagnosis in a large proportion of patients with muscular diseases. Nevertheless, many patients remain unsolved, although the clinical history and/or the muscle biopsy give a clear indication of the involved genes. In many cases, there is a strong suspicion that the cause must lie in unexplored gene areas, such as deep-intronic or other non-coding regions. In order to find these changes, next-generation sequencing (NGS) methods are constantly evolving, making it possible to sequence entire genomes to reveal these previously uninvestigated regions. Here, we present a young woman who was strongly suspected of having a so far genetically unsolved sarcoglycanopathy based on her clinical history and muscle biopsy. Using short read whole genome sequencing (WGS), a homozygous inversion on chromosome 13 involving SGCG and LINC00621 was detected. The breakpoint in intron 2 of SGCG led to the absence of γ-sarcoglycan, resulting in the manifestation of autosomal recessive limb-girdle muscular dystrophy 5 (LGMDR5) in the young woman.
- Published
- 2022
- Full Text
- View/download PDF
38. SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile.
- Author
-
Al-Jawahiri R, Foroutan A, Kerkhof J, McConkey H, Levy M, Haghshenas S, Rooney K, Turner J, Shears D, Holder M, Lefroy H, Castle B, Reis LM, Semina EV, Lachlan K, Chandler K, Wright T, Clayton-Smith J, Hug FP, Pitteloud N, Bartoloni L, Hoffjan S, Park SM, Thankamony A, Lees M, Wakeling E, Naik S, Hanker B, Girisha KM, Agolini E, Giuseppe Z, Alban Z, Tessarech M, Keren B, Afenjar A, Zweier C, Reis A, Smol T, Tsurusaki Y, Nobuhiko O, Sekiguchi F, Tsuchida N, Matsumoto N, Kou I, Yonezawa Y, Ikegawa S, Callewaert B, Freeth M, Kleinendorst L, Donaldson A, Alders M, De Paepe A, Sadikovic B, and McNeill A
- Subjects
- Humans, Phenotype, Exome Sequencing, DNA Methylation genetics, Hypogonadism genetics, Klinefelter Syndrome genetics, Neurodevelopmental Disorders genetics, SOXC Transcription Factors genetics
- Abstract
Purpose: This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants., Methods: Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope., Results: We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies., Conclusion: SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
39. Phoenix from the ashes: dramatic improvement in severe late-onset methylenetetrahydrofolate reductase (MTHFR) deficiency with a complete loss of vision.
- Author
-
Biesalski AS, Hoffjan S, Schneider R, Nguyen HP, Dekomien G, Lücke T, Schneider-Gold C, Matusche B, Gold R, and Ayzenberg I
- Subjects
- Humans, Methylenetetrahydrofolate Reductase (NADPH2) genetics, Muscle Spasticity, Blindness etiology, Methylenetetrahydrofolate Reductase (NADPH2) deficiency
- Published
- 2022
- Full Text
- View/download PDF
40. De novo missense variants in FBXO11 alter its protein expression and subcellular localization.
- Author
-
Gregor A, Meerbrei T, Gerstner T, Toutain A, Lynch SA, Stals K, Maxton C, Lemke JR, Bernat JA, Bombei HM, Foulds N, Hunt D, Kuechler A, Beygo J, Stöbe P, Bouman A, Palomares-Bralo M, Santos-Simarro F, Garcia-Minaur S, Pacio-Miguez M, Popp B, Vasileiou G, Hebebrand M, Reis A, Schuhmann S, Krumbiegel M, Brown NJ, Sparber P, Melikyan L, Bessonova L, Cherevatova T, Sharkov A, Shcherbakova N, Dabir T, Kini U, Schwaibold EMC, Haack TB, Bertoli M, Hoffjan S, Falb R, Shinawi M, Sticht H, and Zweier C
- Subjects
- HEK293 Cells, HeLa Cells, Humans, Mutation, Missense genetics, Protein-Arginine N-Methyltransferases genetics, F-Box Proteins genetics, Intellectual Disability genetics, Neurodevelopmental Disorders genetics
- Abstract
Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data, our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs., (© The Author(s) 2021. Published by Oxford University Press.)
- Published
- 2022
- Full Text
- View/download PDF
41. Association between shorter leukocyte telomeres and multiple sclerosis.
- Author
-
Habib R, Ocklenburg S, Hoffjan S, Haghikia A, Epplen JT, and Arning L
- Subjects
- Adult, Aged, Aging genetics, Case-Control Studies, Female, Humans, Male, Middle Aged, Severity of Illness Index, Sex Characteristics, Leukocytes ultrastructure, Multiple Sclerosis genetics, Telomere Shortening
- Abstract
Relative telomere length (TL) is regarded as a biomarker of biological age. Accelerated immune aging, as represented by TL reduction, has been demonstrated in autoimmune diseases, including multiple sclerosis (MS). However, it is still unresolved whether telomere shortening is the cause or the consequence of the pathogenic events underlying autoimmunity. Assessing TL in whole blood DNA samples in 138 MS patients and 120 healthy controls showed reduced TL in patients as compared with controls There seems to be a prelude of accelerated telomere shortening, which may increase the risk for development of MS., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
42. The Rare IL22RA2 Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis.
- Author
-
Gómez-Fernández P, Lopez de Lapuente Portilla A, Astobiza I, Mena J, Urtasun A, Altmann V, Matesanz F, Otaegui D, Urcelay E, Antigüedad A, Malhotra S, Montalban X, Castillo-Triviño T, Espino-Paisán L, Aktas O, Buttmann M, Chan A, Fontaine B, Gourraud PA, Hecker M, Hoffjan S, Kubisch C, Kümpfel T, Luessi F, Zettl UK, Zipp F, Alloza I, Comabella M, Lill CM, and Vandenbroeck K
- Subjects
- Adult, Amino Acid Sequence, Computer Simulation, Databases, Genetic, Gene Frequency genetics, HEK293 Cells, Humans, Middle Aged, Protein Isoforms genetics, Protein Isoforms metabolism, Receptors, Interleukin chemistry, Risk Factors, Genetic Predisposition to Disease, Multiple Sclerosis genetics, Polymorphism, Single Nucleotide genetics, Protein Sorting Signals genetics, Receptors, Interleukin genetics
- Abstract
The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly ( p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset ( p = 3.17 × 10
-4 ). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%-60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.- Published
- 2020
- Full Text
- View/download PDF
43. Evaluation of variation in genes of the arylhydrocarbon receptor pathway for an association with multiple sclerosis.
- Author
-
Zorlu N, Hoffjan S, Haghikia A, Deyneko IV, and Epplen JT
- Subjects
- Adult, Case-Control Studies, Cohort Studies, Female, Genetic Association Studies methods, Humans, Male, Middle Aged, Basic Helix-Loop-Helix Transcription Factors genetics, Genetic Variation genetics, Multiple Sclerosis diagnosis, Multiple Sclerosis genetics, Polymorphism, Single Nucleotide genetics, Receptors, Aryl Hydrocarbon genetics
- Abstract
The aryl hydrocarbon receptor (AhR) contributes to immune regulation in autoimmune diseases such as multiple sclerosis (MS). Analysis of selected polymorphisms in AhR pathway genes in 805 MS patients and 1023 controls revealed a modest association of a CYP1B1 polymorphism with secondary progressive MS that became more pronounced in combination with other SNPs in the pathway, suggesting interactive effects. Additionally, first evidence for an interaction with smoking was found, but due to small sample sizes statistical significance was only nominal. Confirmation of these results in independent cohorts is recommended, since targeting the AhR constitutes a therapeutic option for autoimmune diseases., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
44. SI: Next-generation sequencing in human molecular genetic diagnostics.
- Author
-
Hoffjan S
- Subjects
- Early Diagnosis, Humans, Sequence Analysis, DNA, Genetic Testing methods, High-Throughput Nucleotide Sequencing methods
- Published
- 2019
- Full Text
- View/download PDF
45. BICD2 mutational analysis in hereditary spastic paraplegia and hereditary motor and sensory neuropathy.
- Author
-
Kropatsch R, Schmidt HM, Buttkereit P, Epplen JT, and Hoffjan S
- Subjects
- Adult, Cohort Studies, Female, Genetic Linkage, Humans, Male, Mutation, Missense genetics, DNA Mutational Analysis, Hereditary Sensory and Motor Neuropathy genetics, Microtubule-Associated Proteins genetics, Spastic Paraplegia, Hereditary genetics
- Abstract
Introduction: Mutations in the BICD2 gene are causative for an autosomal dominant form of spinal muscular atrophy (SMALED2). Further, BICD2 mutations have been implicated in hereditary spastic paraplegia (HSP), but only very few such patients have been described. In this report we aimed to investigate the frequency of BICD2 mutations in patients with HSP and hereditary motor and sensory neuropathy (HMSN) who were negative for the most common known genetic causes., Methods: The cohorts comprised 171 HSP and 189 HMSN patients. Mutational analysis was performed with high-resolution melting analysis followed by Sanger sequencing., Results: In both cohorts, we found no known or likely pathogenic mutations in the BICD2 gene., Discussion: BICD2 mutations appear rather unlikely to cause a phenotype of HMSN and are a very rare cause of the HSP phenotype. Muscle Nerve 59:484-486, 2019., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2019
- Full Text
- View/download PDF
46. TPP2 mutation associated with sterile brain inflammation mimicking MS.
- Author
-
Reinthaler EM, Graf E, Zrzavy T, Wieland T, Hotzy C, Kopecky C, Pferschy S, Schmied C, Leutmezer F, Keilani M, Lill CM, Hoffjan S, Epplen JT, Zettl UK, Hecker M, Deutschländer A, Meuth SG, Ahram M, Mustafa B, El-Khateeb M, Vilariño-Güell C, Sadovnick AD, Zimprich F, Tomkinson B, Strom T, Kristoferitsch W, Lassmann H, and Zimprich A
- Abstract
Objective: To ascertain the genetic cause of a consanguineous family from Syria suffering from a sterile brain inflammation mimicking a mild nonprogressive form of MS., Methods: We used homozygosity mapping and next-generation sequencing to detect the disease-causing gene in the affected siblings. In addition, we performed RNA and protein expression studies, enzymatic activity assays, immunohistochemistry, and targeted sequencing of further MS cases from Austria, Germany, Canada and Jordan., Results: In this study, we describe the identification of a homozygous missense mutation (c.82T>G, p.Cys28Gly) in the tripeptidyl peptidase II ( TPP2 ) gene in all 3 affected siblings of the family. Sequencing of all TPP2 -coding exons in 826 MS cases identified one further homozygous missense variant (c.2027C>T, p.Thr676Ile) in a Jordanian MS patient. TPP2 protein expression in whole blood was reduced in the affected siblings. In contrast, TPP2 protein expression in postmortem brain tissue from MS patients without TPP2 mutations was highly upregulated., Conclusions: The homozygous TPP2 mutation (p.Cys28Gly) is likely responsible for the inflammation phenotype in this family. TPP2 is an ubiquitously expressed serine peptidase that removes tripeptides from the N-terminal end of longer peptides. TPP2 is involved in various biological processes including the destruction of major histocompatibility complex Class I epitopes. Recessive loss-of-function mutations in TPP2 were described in patients with Evans syndrome, a rare autoimmune disease affecting the hematopoietic system. Based on the gene expression results in our MS autopsy brain samples, we further suggest that TPP2 may play a broader role in the inflammatory process in MS.
- Published
- 2018
- Full Text
- View/download PDF
47. Novel Nonsense Mutation in SLC39A13 Initially Presenting as Myopathy: Case Report and Review of the Literature.
- Author
-
Dusanic M, Dekomien G, Lücke T, Vorgerd M, Weis J, Epplen JT, Köhler C, and Hoffjan S
- Abstract
Myopathies comprise a heterogeneous group of disorders characterized by variable phenotypes. The increasing use of next-generation sequencing allows identification of the causative genes in a much higher percentage of patients with hereditary muscle disorders and also illustrates a considerable degree of overlap with other clinical entities, including connective tissue disorders. Here, we present a 14-year-old German patient who was initially suspected to suffer from myopathy based on his clinical, radiological, and muscle biopsy findings. Exome sequencing revealed a novel homozygous nonsense mutation in the SLC39A13 gene, causative for spondylocheiro dysplastic Ehlers Danlos syndrome (SCD-EDS), suggesting a connective tissue disorder. Including our patient, only 9 affected individuals from 4 families have been described for SCD-EDS so far. The previously reported patients did not show obvious evidence of myopathy, suggesting a broader clinical presentation than originally suspected. We summarize herein the current knowledge on clinical features as well as pathophysiological pathways for this rare connective tissue disease and discuss the high degree of clinical overlap between myopathic and connective tissue disorders.
- Published
- 2018
- Full Text
- View/download PDF
48. Frequency of SCA8, SCA10, SCA12, SCA36, FXTAS and C9orf72 repeat expansions in SCA patients negative for the most common SCA subtypes.
- Author
-
Aydin G, Dekomien G, Hoffjan S, Gerding WM, Epplen JT, and Arning L
- Subjects
- Adult, Cohort Studies, Female, Humans, Male, Middle Aged, Young Adult, Ataxia genetics, C9orf72 Protein genetics, DNA Repeat Expansion genetics, Fragile X Syndrome genetics, Nerve Tissue Proteins genetics, Spinocerebellar Ataxias epidemiology, Spinocerebellar Ataxias genetics, Tremor genetics
- Abstract
Background: Spinocerebellar ataxia (SCA) subtypes are often caused by expansions in non-coding regions of genes like SCA8, SCA10, SCA12 and SCA36. Other ataxias are known to be associated with repeat expansions such as fragile X-associated tremor ataxia syndrome (FXTAS) or expansions in the C9orf72 gene. When no mutation has been identified in the aforementioned genes next-generation sequencing (NGS)-based diagnostics may also be applied. In order to define an optimal diagnostic strategy, more information about the frequency and phenotypic characteristics of rare repeat expansion disorders associated with ataxia should be at hand., Methods: We analyzed a consecutive cohort of 440 German unrelated patients with symptoms of cerebellar ataxia, dysarthria and other unspecific symptoms who were referred to our center for SCA diagnostics. They showed alleles in the normal range for the most common SCA subtypes SCA1-3, SCA6, SCA7 and SCA17. These patients were screened for expansions causing SCA8, SCA10, SCA12, SCA36 and FXTAS as well as for the pathogenic hexanucleotide repeat in the C9orf72 gene., Results: Expanded repeats for SCA10, SCA12 or SCA36 were not identified in the analyzed patients. Five patients showed expanded SCA8 CTA/CTG alleles with 92-129 repeats. One 51-year-old male with unclear dementia symptoms was diagnosed with a large GGGGCC repeat expansion in C9orf72. The analysis of the fragile X mental retardation 1 gene (FMR1) revealed one patient with a premutation (>50 CGG repeats) and seven patients with alleles in the grey zone (41 to 54 CGG repeats)., Conclusions: Altogether five patients showed 92 or more SCA8 CTA/CTG combined repeats. Our results support the assumption that smaller FMR1 gene expansions could be associated with the risk of developing neurological signs. The results do not support genetic testing for C9orf72 expansion in ataxia patients.
- Published
- 2018
- Full Text
- View/download PDF
49. First large genomic inversion in familial cerebral cavernous malformation identified by whole genome sequencing.
- Author
-
Spiegler S, Rath M, Hoffjan S, Dammann P, Sure U, Pagenstecher A, Strom T, and Felbor U
- Subjects
- Brain diagnostic imaging, Brain pathology, Child, Genome-Wide Association Study, Hemangioma, Cavernous, Central Nervous System diagnostic imaging, Hemangioma, Cavernous, Central Nervous System pathology, Humans, Male, Pedigree, Whole Genome Sequencing, Carrier Proteins genetics, Chromosome Inversion, Hemangioma, Cavernous, Central Nervous System genetics
- Abstract
Familial cerebral cavernous malformations (CCMs) predispose to seizures and hemorrhagic stroke. Molecular genetic analyses of CCM1, CCM2, and CCM3 result in a mutation detection rate of up to 98%. However, only whole genome sequencing (WGS) in combination with the Manta algorithm for analyses of structural variants revealed a heterozygous 24 kB inversion including exon 1 of CCM2 in a 12-year-old boy with familial CCMs. Its breakpoints were fine-mapped, and quantitative analysis on RNA confirmed reduced CCM2 expression. Our data expand the spectrum of CCM mutations and indicate that the existence of a fourth CCM disease gene is rather unlikely.
- Published
- 2018
- Full Text
- View/download PDF
50. Clinical and Imaging Presentation of a Patient with Beta-Propeller Protein-Associated Neurodegeneration, a Rare and Sporadic form of Neurodegeneration with Brain Iron Accumulation (NBIA).
- Author
-
Hattingen E, Handke N, Cremer K, Hoffjan S, and Kukuk GM
- Subjects
- Adult, Brain, Carrier Proteins genetics, Female, Humans, Iron, Iron Metabolism Disorders complications, Iron Metabolism Disorders genetics, Magnetic Resonance Imaging, Mutation, Missense, Neuroaxonal Dystrophies complications, Neuroaxonal Dystrophies genetics, Pantothenate Kinase-Associated Neurodegeneration, Iron Metabolism Disorders diagnostic imaging, Neuroaxonal Dystrophies diagnostic imaging
- Abstract
Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of inherited neurologic disorders with iron accumulation in the basal ganglia, which share magnetic resonance (MR) imaging characteristics, histopathologic and clinical features. According to the affected basal nuclei, clinical features include extrapyramidal movement disorders and varying degrees of intellectual disability status. The most common NBIA subtype is caused by pathogenic variants in PANK2. The hallmark of MR imaging in patients with PANK2 mutations is an eye-of-the-tiger sign in the globus pallidus. We report a 33-year-old female with a rare subtype of NBIA, called beta-propeller protein-associated neurodegeneration (BPAN) with a hitherto unknown missense variant in WDR45. She presented with BPAN's particular biphasic course of neurological symptoms and with a dominant iron accumulation in the midbrain that enclosed a spotty T2-hyperintensity.
- Published
- 2017
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.