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155 results on '"Yigit, G"'

1. Expanding the spectrum of EEF1D neurodevelopmental disorders: biallelic variants in the guanine exchange domain

Author

Averdunk, L., Al-Thihli, K., Surowy, H., Lüdecke, H.J., Drechsler, M., Yigit, G., Smorag, L., Hallak, B.A., Li, Y., Altmüller, J., Guthoff, T., Wallot, M., Nürnberg, P., Wollnik, B., Abou Jamra, R., Al-Maawali, A., and Wieczorek, D.

Subjects
Technology Platforms
Abstract

Protein translation is an essential cellular process and dysfunctional protein translation causes various neurodevelopmental disorders. The eukaryotic translation elongation factor 1A (eEF1A) delivers aminoacyl-tRNA to the ribosome, while the eEF1B complex acts as a guanine exchange factor (GEF) of GTP for GDP indirectly catalyzing the release of eEF1A from the ribosome. The gene EEF1D encodes the eEF1Bδ subunit of the eEF1B complex. EEF1D is alternatively spliced giving rise to one long and three short isoforms. Two different homozygous, truncating variants in EEF1D had been associated with severe intellectual disability and microcephaly in two families. The published variants only affect the long isoform of EEF1D that acts as a transcription factor of heat shock element proteins. By exome sequencing, we identified two different homozygous variants in EEF1D in two families with severe developmental delay, severe microcephaly, spasticity, and failure to thrive with optic atrophy, poor feeding, and recurrent aspiration pneumonias. The EEF1D variants of this study are localized in the C-terminal GEF domain suggesting that a disturbed protein translation machinery might contribute to the neurodevelopmental phenotype. Pathogenic variants localized in both the alternatively spliced domain or in the GEF domain of EEF1D cause a severe neurodevelopmental disorder with microcephaly and spasticity.

Published
2023

2. Somatic mosaicism in STAG2-associated cohesinopathies: Expansion of the genotypic and phenotypic spectrum

Author

Schmidt, J., Dreha-Kulaczewski, S., Zafeiriou, M.P., Schreiber, M.K., Wilken, B., Funke, R., Neuhofer, C., Altmüller, J., Thiele, H., Nürnberg, P., Biskup, S., Li, Y., Zimmermann, W.H., Kaulfuß, S., Yigit, G., and Wollnik, B.

Subjects
Cell Biology, Technology Platforms, Bioengineered Neuronal Organoids, Cohesinopathies, Mosaic Disorders, Stag2, Supernumerary Nipples, Developmental Biology
Abstract

STAG2 is a component of the large, evolutionarily highly conserved cohesin complex, which has been linked to various cellular processes like genome organization, DNA replication, gene expression, heterochromatin formation, sister chromatid cohesion, and DNA repair. A wide spectrum of germline variants in genes encoding subunits or regulators of the cohesin complex have previously been identified to cause distinct but phenotypically overlapping multisystem developmental disorders belonging to the group of cohesinopathies. Pathogenic variants in STAG2 have rarely been implicated in an X-linked cohesinopathy associated with undergrowth, developmental delay, and dysmorphic features. Here, we describe for the first time a mosaic STAG2 variant in an individual with developmental delay, microcephaly, and hemihypotrophy of the right side. We characterized the grade of mosaicism by deep sequencing analysis on DNA extracted from EDTA blood, urine and buccal swabs. Furthermore, we report an additional female with a novel de novo splice variant in STAG2. Interestingly, both individuals show supernumerary nipples, a feature that has not been reported associated to STAG2 before. Remarkably, additional analysis of STAG2 transcripts in both individuals showed only wildtype transcripts, even after blockage of nonsense-mediated decay using puromycin in blood lymphocytes. As the phenotype of STAG2-associated cohesinopathies is dominated by global developmental delay, severe microcephaly, and brain abnormalities, we investigated the expression of STAG2 and other related components of the cohesin complex during Bioengineered Neuronal Organoids (BENOs) generation by RNA sequencing. Interestingly, we observed a prominent expression of STAG2, especially between culture days 0 and 15, indicating an essential function of STAG2 in early brain development. In summary, we expand the genotypic and phenotypic spectrum of STAG2-associated cohesinopathies and show that BENOs represent a promising model to gain further insights into the critical role of STAG2 in the complex process of nervous system development.

Published
2022

3. Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state

Author

Yigit, G., Sheffer, R., Daana, M., Li, Y., Kaygusuz, E., Mor-Shakad, H., Altmüller, J., Nürnberg, P., Douiev, L., Kaulfuss, S., Burfeind, P., Wollnik, B., and Brockmann, K.

Subjects
Technology Platforms
Abstract

BACKGROUND: Developmental and epileptic encephalopathies (DEEs) represent a group of severe neurological disorders characterised by an onset of refractory seizures during infancy or early childhood accompanied by psychomotor developmental delay or regression. DEEs are genetically heterogeneous with, to date, more than 80 different genetic subtypes including DEE31 caused by heterozygous missense variants in DNM1. METHODS: We performed a detailed clinical characterisation of two unrelated patients with DEE and used whole-exome sequencing to identify causative variants in these individuals. The identified variants were tested for cosegregation in the respective families. RESULTS: We excluded pathogenic variants in known, DEE-associated genes. We identified homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the DNM1 gene, indicating that biallelic, loss-of-function pathogenic variants in DNM1 cause DEE. CONCLUSION: Our finding that homozygous, loss-of-function variants in DNM1 cause DEE expands the spectrum of pathogenic variants in DNM1. All parents who were heterozygous carriers of the identified loss-of-function variants were healthy and did not show any clinical symptoms, indicating that the type of mutation in DNM1 determines the pattern of inheritance.

Published
2022

4. Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies

Author

Iqbal, M, Maroofian, R, Çavdarlı, B, Riccardi, F, Field, M, Banka, S, Bubshait, DK, Li, Y, Hertecant, J, Baig, SM, Dyment, D, Efthymiou, S, Abdullah, U, Makhdoom, EUH, Ali, Z, Scherf de Almeida, T, Molinari, F, Mignon-Ravix, C, Chabrol, B, Antony, J, Ades, L, Pagnamenta, AT, Jackson, A, Douzgou, S, Genomics England Research Consortium, Beetz, C, Karageorgou, V, Vona, B, Rad, A, Baig, JM, Sultan, T, Alvi, JR, Maqbool, S, Rahman, F, Toosi, MB, Ashrafzadeh, F, Imannezhad, S, Karimiani, EG, Sarwar, Y, Khan, S, Jameel, M, Noegel, AA, Budde, B, Altmüller, J, Motameny, S, Höhne, W, Houlden, H, Nürnberg, P, Wollnik, B, Villard, L, Alkuraya, FS, Osmond, M, Hussain, MS, and Yigit, G

Abstract

PURPOSE: We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. METHODS: We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable. RESULTS: In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4. CONCLUSION: We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans.

Published
2021

7. Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

Author

Kargapolova, Y., Rehimi, R., Kayserili, H., Brühl, J., Sofiadis, K., Zirkel, A., Palikyras, S., Mizi, A., Li, Yun, Yigit, G., Hoischen, A., Frank, S., Russ, N., Trautwein, J., Bon, B. van, Gilissen, C.F., Laugsch, M., Gusmao, E.G., Josipovic, N., Altmüller, J., Nürnberg, P., Längst, G., Kaiser, F.J., Watrin, E., Brunner, H.G., Rada-Iglesias, A., Kurian, L., Wollnik, B., Bouazoune, K., Papantonis, A., Kargapolova, Y., Rehimi, R., Kayserili, H., Brühl, J., Sofiadis, K., Zirkel, A., Palikyras, S., Mizi, A., Li, Yun, Yigit, G., Hoischen, A., Frank, S., Russ, N., Trautwein, J., Bon, B. van, Gilissen, C.F., Laugsch, M., Gusmao, E.G., Josipovic, N., Altmüller, J., Nürnberg, P., Längst, G., Kaiser, F.J., Watrin, E., Brunner, H.G., Rada-Iglesias, A., Kurian, L., Wollnik, B., Bouazoune, K., and Papantonis, A.

Abstract

Contains fulltext : 235041.pdf (Publisher’s version ) (Open Access), Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers implicated in human pathologies, with CHD6 being one of its least studied members. We discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. By combining genomics with functional in vivo and in vitro assays, we show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS mutation affects CHD6 protein folding and impairs its ability to recruit co-remodelers in response to DNA damage or autophagy stimulation. This leads to accumulation of DNA damage burden and senescence-like phenotypes. We therefore uncovered a molecular mechanism explaining HSS onset via chromatin control of autophagic flux and genotoxic stress surveillance.

Published
2021

8. Evidence of pathogenicity for the leaky splice variant c.1066-6T>G in ATM

Author

Schröder, S., Wieland, B., Ohlenbusch, A., Yigit, G., Altmüller, J., Boltshauser, E., Dörk, T., and Brockmann, K.

Subjects
Technology Platforms
Abstract

Mild clinical phenotypes of ataxia-telangiectasia (variant A-T) are associated with biallelic ATM variants resulting in residual function of the ATM kinase. At least one regulatory, missense, or leaky splice site mutation resulting in expression of ATM with low level kinase activity was identified in subjects with variant A-T. Studies on the pathogenicity of the germline splicing ATM variant c.1066-6T>G have provided conflicting results. Using whole-exome sequencing, we identified two splice site ATM variants, c.1066-6T>G; [p.?], and c.2250G>A, [p.Ile709_Lys750del], in a compound heterozygous state in a 27-year-old woman who had been diagnosed as having congenital ocular motor apraxia type Cogan in her childhood. Reappraisal of her clinical phenotype revealed consistency with variant A-T. Functional analyses showed reduced expression of ATM protein and residual activity of the ATM kinase at a level consistent with variant A-T. Our results provide evidence for pathogenicity of the leaky ATM splice site variant c.1066-6T>G.

Published
2020

9. Human RAD50 deficiency: Confirmation of a distinctive phenotype

Author

Ragamin, A. (Aviël), Yigit, G. (Gökhan), Bousset, K. (Kristine), Beleggia, F. (Filippo), Verheijen, F.W. (Frans), Wit, M.C.Y. (Marie Claire) de, Strom, T.M. (Tim M.), Dörk, T. (Thilo), Wollnik, B. (Bernd), Mancini, G.M.S. (Grazia), Ragamin, A. (Aviël), Yigit, G. (Gökhan), Bousset, K. (Kristine), Beleggia, F. (Filippo), Verheijen, F.W. (Frans), Wit, M.C.Y. (Marie Claire) de, Strom, T.M. (Tim M.), Dörk, T. (Thilo), Wollnik, B. (Bernd), and Mancini, G.M.S. (Grazia)

Abstract

DNA double-strand breaks (DSBs) are highly toxic DNA lesions that can lead to chromosomal instability, loss of genes and cancer. The MRE11/RAD50/NBN (MRN) complex is keystone involved in signaling processes inducing the repair of DSB by, for example, in activating pathways leading to homologous recombination repair and nonhomologous end joining. Additionally, the MRN complex also plays an important role in the maintenance of telomeres and can act as a stabilizer at replication forks. Mutations in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)-like disorder, respectively. So far, only one single patient with biallelic loss of function variants in RAD50 has been reported presenting with features classified as NBS-like disorder. Here, we report a long-term follow-up of an unrelated patient with facial dysmorphisms, microcephaly, skeletal features, and short stature who is homozygous for a novel variant in RAD50. We could show that this variant, c.2524G > A in exon 15 of the RAD50 gene, induces aberrant splicing of RAD50 mRNA mainly leading to premature protein truncation and thereby, most likely, to loss of RAD50 function. Using patient-derived primary fibroblasts, we could show abnormal radioresistant DNA synthesis confirming pathogenicity of the identified variant. Immunoblotting experiments showed strongly reduced protein levels of RAD50 in the pat

Published
2020
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10. Severe Osteogenesis imperfecta with oligodontia: think of MESD

Author

Moosa, S., Yamamoto, G. L., Garbes, L., Keupp, K., Beleza-Meireles, A., Moreno, C. A., Valadares, E. R., de Sousa, S. B., Maia, S., Saraiva, J., Honjo, R. S., Kim, C. A., Cabral de Menezes, H., Lausch, E., Lorini, P. V., Lamounier, A., Jr., Carniero, T. C. B., Giunta, C., Rohrbach, M., Janner, M., Semler, O., Beleggia, F., Li, Y., Yigit, G., Reintjes, N., Altmuller, J., Nurnberg, P., Cavalcanti, D. P., Zabel, B., Warman, M. L., Bertola, D. R., Wollnik, B., Netzer, C., Moosa, S., Yamamoto, G. L., Garbes, L., Keupp, K., Beleza-Meireles, A., Moreno, C. A., Valadares, E. R., de Sousa, S. B., Maia, S., Saraiva, J., Honjo, R. S., Kim, C. A., Cabral de Menezes, H., Lausch, E., Lorini, P. V., Lamounier, A., Jr., Carniero, T. C. B., Giunta, C., Rohrbach, M., Janner, M., Semler, O., Beleggia, F., Li, Y., Yigit, G., Reintjes, N., Altmuller, J., Nurnberg, P., Cavalcanti, D. P., Zabel, B., Warman, M. L., Bertola, D. R., Wollnik, B., and Netzer, C.

Published
2020

12. Epileptic encephalopathy due to BRAT1 pathogenic variants: report of eight new patients

Author

Piard, J., Moris-Rosendahl, D. J., Putoux, A., Delplancq, G., Cabrol, C., Goffeney, J. Belleville, Pasquier, L., Brischoux-Boucher, E., Bernd Wollnik, Yigit, G., Albrecht, B., Lesca, G., Villard, L., Edery, P., Sanlaville, D., Streichenberger, N., Altuzarra, C., Harms, F. L., Kutsche, K., Maldergem, L., Gall, Valérie, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut NeuroMyoGène (INMG), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Génétique Humaine, Université de Liège-CHU Liège, Service de génétique clinique, hôpital Sud, Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB)

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.GEN] Life Sciences [q-bio]/Genetics
Abstract

51st Conference of the European-Society-of-Human-Genetics (ESHG) in conjunction with the European Meeting on Psychosocial Aspects of Genetics (EMPAG), Milan, ITALY, JUN 16-19, 2018; International audience

Published
2019

13. Mutations in TOP3A Cause a Bloom Syndrome-like Disorder (vol 103, pg 221, 2018)

Author

Martin, CA, Sarlos, K, Logan, CV, Thakur, RS, Parry, DA, Bizard, AH, Leitch, A, Cleal, L, Ali, NS, Al-Owain, MA, Allen, W, Altmuller, J, Aza-Carmona, M, Barakat, BAY, Barraza-Garcia, J, Begtrup, A, Bogliolo, M, Cho, MT, Cruz-Rojo, J, Dhahrabi, HAM, Elcioglu, NH, GOSgene, Gorman, GS, Jobling, R, Kesterton, I, Kishita, Y, Kohda, M, Stabej, PLQ, Malallah, AJ, Nurnberg, P, Ohtake, A, Okazaki, Y, Pujol, R, Ramirez, MJ, Revah-Politi, A, Shimura, M, Stevens, P, Taylor, RW, Turner, L, Williams, H, Wilson, C, Yigit, G, Zahavich, L, Alkuraya, FS, Surralles, J, Iglesias, A, Murayama, K, Wollnik, B, Dattani, M, Heath, KE, Hickson, ID, and Jackson, AP

Published
2018

16. De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Author

Gordon, C, Xue, S, Yigit, G, Filali, H, Chen, K, Rosin, N, Yoshiura, K, Oufadem, M, Beck, T, McGowan, R, Magee, A, Altmuller, J, Dion, C, Thiele, H, Gurzau, A, Nurnberg, P, Meschede, D, Muhlbauer, W, Okamoto, N, Varghese, V, Irving, R, Sigaudy, S, Williams, D, Ahmed, F, Bonnard, C, Kei Kong, M, Ratbi, I, Fejjal, N, Fikri, M, Chafai Elalaoui, S, Reigstad, H, Bole-Feysot, C, Nitschke, P, Ragge, N, Levy, N, Tuncbilek, G, Teo, A, Cunningham, M, Sefiani, A, Kayserili, H, Murphy, J, Chatdokmaiprai, C, Hillmer, A, Wattanasirichaigoon, D, Lyonnet, S, Magdinier, F, Javed, A, Blewitt, M, Amiel, J, Wollnik, B, Reversade, B, Gordon, C, Xue, S, Yigit, G, Filali, H, Chen, K, Rosin, N, Yoshiura, K, Oufadem, M, Beck, T, McGowan, R, Magee, A, Altmuller, J, Dion, C, Thiele, H, Gurzau, A, Nurnberg, P, Meschede, D, Muhlbauer, W, Okamoto, N, Varghese, V, Irving, R, Sigaudy, S, Williams, D, Ahmed, F, Bonnard, C, Kei Kong, M, Ratbi, I, Fejjal, N, Fikri, M, Chafai Elalaoui, S, Reigstad, H, Bole-Feysot, C, Nitschke, P, Ragge, N, Levy, N, Tuncbilek, G, Teo, A, Cunningham, M, Sefiani, A, Kayserili, H, Murphy, J, Chatdokmaiprai, C, Hillmer, A, Wattanasirichaigoon, D, Lyonnet, S, Magdinier, F, Javed, A, Blewitt, M, Amiel, J, Wollnik, B, and Reversade, B

Abstract

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.

Published
2017

17. Mutation update for Kabuki syndrome genes KMT2D and KDM6A and further delineation of X-Linked Kabuki Syndrome subtype 2

Author

Bögershausen, N., Gatinois, V., Riehmer, V., Kayserili, H., Becker, J., Thoenes, M., Simsek-Kiper, P.Ö., Barat-Houari, M., Elcioglu, N.H., Wieczorek, D., Tinschert, S., Sarrabay, G., Strom, T.M., Fabre, A., Baynam, G., Sanchez, E., Nürnberg, G., Altunoglu, U., Capri, Y., Isidor, B., Lacombe, D., Corsini, C., Cormier-Daire, V., Sanlaville, D., Giuliano, F., Le Quan Sang, K-H, Kayirangwa, H., Nürnberg, P., Meitinger, T., Boduroglu, K., Zoll, B., Lyonnet, S., Tzschach, A., Verloes, A., Di Donato, N., Touitou, I., Netzer, C., Li, Y., Geneviève, D., Yigit, G., Wollnik, B., Bögershausen, N., Gatinois, V., Riehmer, V., Kayserili, H., Becker, J., Thoenes, M., Simsek-Kiper, P.Ö., Barat-Houari, M., Elcioglu, N.H., Wieczorek, D., Tinschert, S., Sarrabay, G., Strom, T.M., Fabre, A., Baynam, G., Sanchez, E., Nürnberg, G., Altunoglu, U., Capri, Y., Isidor, B., Lacombe, D., Corsini, C., Cormier-Daire, V., Sanlaville, D., Giuliano, F., Le Quan Sang, K-H, Kayirangwa, H., Nürnberg, P., Meitinger, T., Boduroglu, K., Zoll, B., Lyonnet, S., Tzschach, A., Verloes, A., Di Donato, N., Touitou, I., Netzer, C., Li, Y., Geneviève, D., Yigit, G., and Wollnik, B.

Abstract

Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up-to-date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well-defined X-linked KS type 2, and comment on phenotype–genotype correlations as well as sex-specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki-like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients.

Published
2016

19. Extreme growth failure is a common presentation of ligase IV deficiency

Author

Murray, J.E., Bicknell, L.S., Yigit, G., Duker, A.L., Kogelenberg, M. van, Haghayegh, S., Wieczorek, D., Kayserili, H., Albert, M.H., Wise, C.A., Brandon, J., Kleefstra, T., Warris, A., Flier, M. van der, Bamforth, J.S., Doonanco, K., Ades, L., Ma, A., Field, M., Johnson, D., Shackley, F., Firth, H., Woods, C.G., Nurnberg, P., Gatti, R.A., Hurles, M., Bober, M.B., Wollnik, B., Jackson, A.P., Murray, J.E., Bicknell, L.S., Yigit, G., Duker, A.L., Kogelenberg, M. van, Haghayegh, S., Wieczorek, D., Kayserili, H., Albert, M.H., Wise, C.A., Brandon, J., Kleefstra, T., Warris, A., Flier, M. van der, Bamforth, J.S., Doonanco, K., Ades, L., Ma, A., Field, M., Johnson, D., Shackley, F., Firth, H., Woods, C.G., Nurnberg, P., Gatti, R.A., Hurles, M., Bober, M.B., Wollnik, B., and Jackson, A.P.

Abstract

Contains fulltext : 138015.pdf (publisher's version ) (Open Access), Ligase IV syndrome is a rare differential diagnosis for Nijmegen breakage syndrome owing to a shared predisposition to lympho-reticular malignancies, significant microcephaly, and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC -10.1 s.d., height -5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype-phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder.

Published
2014

20. Mutations in the interleukin receptorcause autosomal recessive Crouzon-like craniosynostosis

Author

Keupp, K, Li, Y, Vargel, I, Hoischen, A, Richardson, R, Neveling, K, Alanay, Y, Uz, E, Elcioğlu, N, Rachwalski, M, Kamaci, S, Tunçbilek, G, Akin, B, Grötzinger, J, Konas, E, Mavili, E, Müller-Newen, G, Collmann, H, Roscioli, T, Buckley, MF, Yigit, G, Gilissen, C, Kress, W, Veltman, J, Hammerschmidt, M, Akarsu, NA, Wollnik, B, Keupp, K, Li, Y, Vargel, I, Hoischen, A, Richardson, R, Neveling, K, Alanay, Y, Uz, E, Elcioğlu, N, Rachwalski, M, Kamaci, S, Tunçbilek, G, Akin, B, Grötzinger, J, Konas, E, Mavili, E, Müller-Newen, G, Collmann, H, Roscioli, T, Buckley, MF, Yigit, G, Gilissen, C, Kress, W, Veltman, J, Hammerschmidt, M, Akarsu, NA, and Wollnik, B

Published
2013

21. Mutations in WNT1 cause different forms of bone fragility

Author

Keupp, K., Beleggia, F., Kayserili, H., Barnes, A., Steiner, M., Semler, O., Fischer, B., Yigit, G., Janda, C., Becker, J., Breer, S., Altunoglu, U., Grünhagen, J., Krawitz, P., Hecht, J., Schinke, T., Makareeva, E., Lausch, E., Cankaya, T., Caparrós-Martín, Jose, Lapunzina, P., Temtamy, S., Aglan, M., Zabel, B., Eysel, P., Koerber, F., Leikin, S., Garcia, K., Netzer, C., Schönau, E., Ruiz-Perez, V., Mundlos, S., Amling, M., Kornak, U., Marini, J., Wollnik, B., Keupp, K., Beleggia, F., Kayserili, H., Barnes, A., Steiner, M., Semler, O., Fischer, B., Yigit, G., Janda, C., Becker, J., Breer, S., Altunoglu, U., Grünhagen, J., Krawitz, P., Hecht, J., Schinke, T., Makareeva, E., Lausch, E., Cankaya, T., Caparrós-Martín, Jose, Lapunzina, P., Temtamy, S., Aglan, M., Zabel, B., Eysel, P., Koerber, F., Leikin, S., Garcia, K., Netzer, C., Schönau, E., Ruiz-Perez, V., Mundlos, S., Amling, M., Kornak, U., Marini, J., and Wollnik, B.

Abstract

We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated ß-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis. © 2013 The American Society of Human Genetics.

Published
2013

22. Molecular mechanisms underlying Seckel syndrome

Author

Yigit, G., Wollnik, B., Yigit, G., and Wollnik, B.

Abstract

Seckel syndrome is an autosomal recessive disorder characterized by proportionately short stature, severe microcephaly, mental retardation and craniofacial deformities that give rise to the typical bird head appearance. In some patients, premature onset of aging-associated diseases is also observed. In terms of genetics, Seckel syndrome is a heterogeneous condition for which many causal genes have been identified in recent years. In addition to genes involved in cellular activities, these include genes with important roles in cell division processes and the activation of DNA damage responses.

Published
2012

23. CEP152 is a genome maintenance protein disrupted in Seckel syndrome

Author

Kalay, E., Yigit, G., Aslan, Y., Brown, K.E., Pohl, E., Bicknell, L.S., Kayserili, H., Li, Y., Tuysuz, B., Nurnberg, G., Kiess, W., Koegl, M., Baessmann, I., Buruk, K., Toraman, B., Kayipmaz, S., Kul, S., Ikbal, M., Turner, D.J., Taylor, M.S., Aerts, J., Scott, C., Milstein, K., Dollfus, H., Wieczorek, D., Brunner, H.G., Hurles, M., Jackson, A.P., Rauch, A., Nurnberg, P., Karaguzel, A., Wollnik, B., Kalay, E., Yigit, G., Aslan, Y., Brown, K.E., Pohl, E., Bicknell, L.S., Kayserili, H., Li, Y., Tuysuz, B., Nurnberg, G., Kiess, W., Koegl, M., Baessmann, I., Buruk, K., Toraman, B., Kayipmaz, S., Kul, S., Ikbal, M., Turner, D.J., Taylor, M.S., Aerts, J., Scott, C., Milstein, K., Dollfus, H., Wieczorek, D., Brunner, H.G., Hurles, M., Jackson, A.P., Rauch, A., Nurnberg, P., Karaguzel, A., and Wollnik, B.

Abstract

Item does not contain fulltext, Functional impairment of DNA damage response pathways leads to increased genomic instability. Here we describe the centrosomal protein CEP152 as a new regulator of genomic integrity and cellular response to DNA damage. Using homozygosity mapping and exome sequencing, we identified CEP152 mutations in Seckel syndrome and showed that impaired CEP152 function leads to accumulation of genomic defects resulting from replicative stress through enhanced activation of ATM signaling and increased H2AX phosphorylation.

Published
2011

29. Sudden bilateral hearing loss after spinal anaesthesia.

Author

Sahin, C, Terzioglu, U, and Yigit, G

Subjects
DIAGNOSIS of deafness, AUDIOMETRY, ORTHOPEDIC surgery, SPINAL anesthesia, SURGICAL complications
Abstract

Background:Spinal anaesthesia is one of the most widely used regional anaesthesia techniques. Sudden bilateral hearing loss following spinal anaesthesia has only been reported in a few cases.Case report:This paper reports the case of a 50-year-old woman who developed sudden bilateral hearing loss following spinal anaesthesia for hallux valgus orthopaedic surgery. This is followed by a literature review.Results:The patient's hearing improved almost completely on the morning of the 3rd day following surgery. No recurrence of hearing loss, tinnitus or vertigo was reported during the six-month follow-up period.Conclusion:Some complications regarding hearing may emerge after spinal anaesthesia. The possibility of hearing loss after spinal anaesthesia should be taken into consideration. Complaints such as hearing loss, tinnitus or vertigo should be taken seriously when reported, and the patient should be referred to an ENT clinic. This will ensure early diagnosis and treatment. [ABSTRACT FROM PUBLISHER]

Published
2015
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34. The effects of experimental hypothyroidism on hemorheology and plasma fibrinogen concentration.

Author

Toplan, S., Dariyerli, N., Ozdemir, S., Akyolcu, M., Hatemi, H., and Yigit, G.

Subjects
HYPOTHYROIDISM, METABOLISM, HEMATOLOGY
Abstract

The effects of experimental hypothyroidism on hemorheology and plasma fibrinogen concentration Thyroid hormones are responsible for arrangement of general body metabolism. In their deficiency pathological findings arise related to various physiological systems. In hypothroid cases it has been observed that blood rheology alters. Hematological changes, especially anemia, are common and well characterized in hypothyroidism. This study has been planned with the purpose to determine the effects of experimental hypothyroidsm on hemorheological parameters and fibrinogen concentration. In this study, twenty Spraque-Dawley type albino female rats weighing 160-200g were used in both control and experimental group animals. Both control (n=10) and experimental group (n=10) animals were kept in same physical conditions during experimental period and were fed with standard fodder and tap water. To induce hypothyroidism, methimazole (75-mg/100g fodder) was given to experimental group rats for 20 days. At the end of the experimental period, blood samples were drawn from the abdominal aorta of the rats under the light ether anesthesia. Thyroid stimulant hormone (TSH), triiodothyronine (T3), thyroxine (T4) hormone levels, hematocrit (% Hct), hemoglobin (Hb), blood viscosity, erythrocyte rigidity index, plasma viscosity and plasma fibrinogen concentration values of both control and experimental group animals were determined and evaluated. Statistical analysis was done by the Mann-Whitney U test. Data were expressed as means ±SD. Differences between groups were considered significant at the p<0.05 level. According to results of our study when values of control group and experimental groups were compared: While T3 and T4 levels of experimental group were found lower (p<0.001) but TSH level higher (p<0.001) than that of the control group. Statistically significant decreased T3, T4 and increased TSH values in experimental group were taken as the indicator of the primary hypothyroidism. Plasma viscosity and fibrinogen concentration of hypothyroid group were found significantly higher than controls (p<0.01). Hematocrit and hemoglobin values were also found lower in experimental group than the control group animals (p<0.01). However, there was no significant difference found in blood viscosity at the original Hct value but there was a significant increase at standart Hct value (p<0.01). There was also no change in erythrocyte rigidity index between control and experimental groups. According to results of our study it may be concluded that in the early phase of hypothyroidism, changes in hemorheology are only seen as an increase in plasma viscosity. Such an increase may be dependent on increased fibrinogen concentration. [ABSTRACT FROM AUTHOR]

Published
2013

35. Erythrocyte osmotic fragility and lipid peroxidation in experimental hyperthyroidism.

Author

Dariyerli, N., Yucel, R., Ozdemir, S., Toplan, S., Akyolcu, M., and Yigit, G.

Subjects
ERYTHROCYTES, METABOLISM, ANTIOXIDANTS
Abstract

Erythrocyte osmotic fragility and lipid peroxidation in experimental hyperthyroidism Thyroid hormones have multifaceted effects on humans. Among others, they influence the basal metabolic rate; the overproduction of thyroid gland hormones results in an increased rate of metabolism and oxygen consumption by cells. Increased thyroid hormone concentrations affect the oxidant/ antioxidant equilibrium and may cause harm to the cell. Thyroid hormones, while leading to increase in free radicals also activate the antioxidant enzymes. The purpose of this study is to determine the structural integrity of red blood cells in experimental hyperthyroidism by assessing the osmotic fragility of erythrocytes in primary hyperthyroidism and its relation between lipid peroxidation. In this study, twenty-two Spraque-Dawley-type female rats weighing between 160 and 200 g were divided into two, as control (n=10) and experimental (n=12), groups. The experimental group animals have received tap water and L-Tiroksin (0.4 mg/100 g fodder) added standard fodder for 30 days to induce hyperthyroidism. Control group animals were fed tap water and standard fodder for the same period. At the end of the experimental period, blood samples were drawn from the abdominal aorta of the rats under light ether anesthesia. Triiodothyronine (T3), thyroxine (T4), and thyroid stimulant hormone (TSH) levels, osmotic fragility, malondialdehyde (MDA), glutathione (GSH) levels and superoxide dismutase (SOD) activity were measured. Statistical analysis was done by Mann-Whitney U test. Data were expressed as means ±SD. Differences between groups were considered significant at the (p<0.05) level. The statistically significant increase in T3, T4 and the significant decrease in TSH) of experimental group is the evidence of induced primary hyperthyroidism. There was a statistically significant increase found in erythrocyte MDA(p<0.001) levels, and SOD activity (p<0.001), but statistically a significant decrease was detected in GSH (p<0.05) levels in hyperthyroid group when compared to controls. In the controls, the osmotic fragility levels were found to be maximum at 0.32 % NaCl and minimum at 0.56 % NaCl, whereas in experimental group reached a maximum at 0.40 % NaCl and minimum at 0.64 %. When statistical evaluations were compared, statistically important increases were detected in maximum and minimum osmotic fragility limits between both the groups (p<0.001). This finding, which shows maximum hemolysis ratio, is the evidence of increased osmotic fragility of the erythrocytes in hyperthyroidism. As a result of our study, it may be concluded that hyperthyroidism may led to an increase in osmotic fragility of erythrocytes and this situation may possibly originate from the increased lipid peroxidation in hyperthyroidism. [ABSTRACT FROM AUTHOR]

Published
2013

40. Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability

Author

Gökhan Yigit, Filippo Beleggia, Janine Altmüller, Nadine Rosin, Pinar Isguven, Peter Nürnberg, Katharina Steindl, Pascal Joset, Nursel Elcioglu, Holger Thiele, Bernd Wollnik, Anita Rauch, University of Zurich, Wollnik, Bernd, Rosin, Nadine, Elcioglu, Nursel H., Beleggia, Filippo, Isguven, Pinar, Altmueller, Janine, Thiele, Holger, Steindl, Katharina, Joset, Pascal, Rauch, Anita, Nuernberg, Peter, Yigit, Goekhan, Rosin, N, Elcioglu, NH, Beleggia, F, Isguven, P, Altmuller, J, Thiele, H, Steindl, K, Joset, P, Rauch, A, Nurnberg, P, Wollnik, B, Yigit, G, Sakarya Üniversitesi/Tıp Fakültesi/Dahili Tıp Bilimleri Bölümü, and İşgüven, Şükriye Pınar

Subjects
Genome instability, Male, V(D)J RECOMBINATION, Microcephaly, 2716 Genetics (clinical), COMET ASSAY, Adolescent, Turkey, IMPACT, 10039 Institute of Medical Genetics, PROTEIN, 610 Medicine & health, Biology, medicine.disease_cause, Compound heterozygosity, Short stature, Genomic Instability, Exon, 1311 Genetics, MAMMALIAN-CELLS, Genetics, medicine, 1312 Molecular Biology, Humans, Point Mutation, Child, Molecular Biology, Genetics (clinical), Genetics & Heredity, Mutation, IMMUNODEFICIENCY, COMPLEX, IDENTIFICATION, Point mutation, Infant, General Medicine, DNA repair protein XRCC4, medicine.disease, Body Height, DNA-Binding Proteins, Phenotype, STRAND BREAK REPAIR, DNA-LIGASE-IV, 570 Life sciences, biology, Female, medicine.symptom
Abstract

DNA double-strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can give rise to genomic instability. Non-homologous end-joining (NHEJ), a well-orchestrated, multistep process involving numerous proteins essential for cell viability, represents one major pathway to repair DSBs in mammalian cells, and mutations in different NHEJ components have been described in microcephalic syndromes associated, e.g. with short stature, facial dysmorphism and immune dysfunction. By using whole-exome sequencing, we now identified in three affected brothers of a consanguineous Turkish family a homozygous mutation, c.482G > A, in the XRCC4 gene encoding a crucial component of the NHEJ pathway. Moreover, we found one additional patient of Swiss origin carrying the compound heterozygous mutations c.25delG (p.His9Thrfs*8) and c.823C > T (p.Arg275*) in XRCC4. The clinical phenotype presented in these patients was characterized by severe microcephaly, facial dysmorphism and short stature, but they did not show a recognizable immunological phenotype. We showed that the XRCC4 c.482G > A mutation, which affects the last nucleotide of exon 4, induces defective splicing of XRCC4 pre-mRNA mainly resulting in premature protein truncation and most likely loss of XRCC4 function. Moreover, we observed on cellular level that XRCC4 deficiency leads to hypersensitivity to DSB-inducing agents and defective DSB repair, which results in increased cell death after exposure to genotoxic agents. Taken together, our data provide evidence that autosomal recessive mutations in XRCC4 induce increased genomic instability and cause a NHEJ-related syndrome defined by facial dysmorphism, primary microcephaly and short stature.

Published
2015

41. Functional characterization of PI3K C2 domain mutations detected in breast cancer circulating tumor cells and metastatic cells.

Author

Smit DJ, Brauer H, Horn S, Yigit G, Haider MT, Pogenberg V, Schumacher U, Pantel K, and Jücker M

Subjects
Humans, Female, Cell Line, Tumor, Neoplasm Metastasis, Protein Domains, Proto-Oncogene Proteins c-akt metabolism, Cell Proliferation, Cell Movement genetics, Phosphatidylinositol 3-Kinases metabolism, Phosphatidylinositol 3-Kinases genetics, Breast Neoplasms genetics, Breast Neoplasms pathology, Neoplastic Cells, Circulating metabolism, Neoplastic Cells, Circulating pathology, Class I Phosphatidylinositol 3-Kinases genetics, Class I Phosphatidylinositol 3-Kinases metabolism, Mutation
Abstract

Background: In breast cancer, over one third of all patients harbor a somatic mutation in the PIK3CA gene, encoding the p110α catalytic subunit of the phosphatidylinositol 3-kinase (PI3K) in their tumor cells. Circulating tumor cells (CTCs) are cells shed from the primary tumor into the blood stream. Recently, the long-term stable breast cancer CTC-ITB-01 cell line with tumorigenic and metastatic capacity was established from liquid biopsy derived cells. The oncogenic hotspot PIK3CA mutation H1047R (kinase domain) was detected in the primary tumor, CTCs and metastasis of the same patient. Other PIK3CA mutations located within the C2 domain (E418K and E453K) were detected in the CTCs and the vaginal metastasis but not in the primary tumor. The goal of our study was to functionally characterize the impact of the rare E418K and E453K mutations within the C2 domain that were not detected in the primary tumor., Methods: PIK3CA mutations E418K, E453K, H1047R were generated by site-directed mutagenesis and stably overexpressed in breast cancer cells by lentiviral transduction. Subsequent signaling pathway activation was examined by western blot analysis. The impact of PIK3CA mutations on biological processes was studied by live cell imaging using the Incucyte Zoom system. Structural modeling was conducted in Pymol. The membrane localization of the mutants was evaluated by separating the cytosolic and membrane fraction using ultracentrifugation. Drug susceptibility of CTC-ITB-01 cells was analyzed by live cell imaging., Results: Western blot analysis of human MDA-MB-231, MCF-7 and T47D breast cancer cells stably overexpressing either the PIK3CA wildtype (WT) or one of the E418K, E453K or H1047R mutants revealed a significant increase in AKT phosphorylation in both C2 mutants (E418K and E453K) and the kinase domain mutant H1047R. Functional analysis showed a significantly increased proliferation of MDA-MB-231 cells overexpressing the E453K and H1047R mutants. Migration was increased in all cells overexpressing WT and each of the mutants. Interestingly, invasion and chemotaxis were only enhanced in the MDA-MB-231 cells overexpressing the C2 domain mutants, i.e. E418K and E453K. In addition, membrane localization of the two C2 domain mutants was increased. Structural modeling of the E453K mutation suggests a disruption of the interaction between the negative regulatory domain of the p85α subunit and the p110α catalytic subunit as a potential mechanism leading to the observed activation of PI3K/AKT/mTOR signaling. Dual targeting of AKT/mTOR pathway by MK2206 and RAD001 leads to very strong synergistic effects (IC 50 MK2206: 148 nM, IC 50 RAD001: 15 nM) with respect to proliferation in the CTC-ITB-01 line through apoptosis induction., Conclusions: Our results demonstrate that PIK3CA C2 domain mutations activate PI3K downstream AKT signaling and can increase proliferation, migration and invasion after stable lentiviral transduction. Although both investigated mutations - E418K and E453K - are located within the C2 domain, a different molecular mechanism can be proposed. The PIK3CA mutated CTC-ITB-01 shows a high susceptibility against dual inhibition of AKT/mTOR. Further studies are required to fully elucidate the oncogenic potential of rare PIK3CA mutations., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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42. Mutations in TOP3A Cause a Bloom Syndrome-like Disorder.

Author

Martin CA, Sarlós K, Logan CV, Thakur RS, Parry DA, Bizard AH, Leitch A, Cleal L, Ali NS, Al-Owain MA, Allen W, Altmüller J, Aza-Carmona M, Barakat BAY, Barraza-García J, Begtrup A, Bogliolo M, Cho MT, Cruz-Rojo J, Mundi Dhahrabi HA, Elcioglu NH, GOSgene, Gorman GS, Jobling R, Kesterton I, Kishita Y, Kohda M, Le Quesne Stabej P, Malallah AJ, Nürnberg P, Ohtake A, Okazaki Y, Pujol R, Ramirez MJ, Revah-Politi A, Shimura M, Stevens P, Taylor RW, Turner L, Williams H, Wilson C, Yigit G, Zahavich L, Alkuraya FS, Surralles J, Iglesias A, Murayama K, Wollnik B, Dattani M, Heath KE, Hickson ID, and Jackson AP

Published
2024
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43. The challenges of research data management in cardiovascular science: a DGK and DZHK position paper-executive summary.

Author

Steffens S, Schröder K, Krüger M, Maack C, Streckfuss-Bömeke K, Backs J, Backofen R, Baeßler B, Devaux Y, Gilsbach R, Heijman J, Knaus J, Kramann R, Linz D, Lister AL, Maatz H, Maegdefessel L, Mayr M, Meder B, Nussbeck SY, Rog-Zielinska EA, Schulz MH, Sickmann A, Yigit G, and Kohl P

Subjects
Humans, Data Management, Reproducibility of Results, Heart, Cardiovascular System, Biomedical Research
Abstract

The sharing and documentation of cardiovascular research data are essential for efficient use and reuse of data, thereby aiding scientific transparency, accelerating the progress of cardiovascular research and healthcare, and contributing to the reproducibility of research results. However, challenges remain. This position paper, written on behalf of and approved by the German Cardiac Society and German Centre for Cardiovascular Research, summarizes our current understanding of the challenges in cardiovascular research data management (RDM). These challenges include lack of time, awareness, incentives, and funding for implementing effective RDM; lack of standardization in RDM processes; a need to better identify meaningful and actionable data among the increasing volume and complexity of data being acquired; and a lack of understanding of the legal aspects of data sharing. While several tools exist to increase the degree to which data are findable, accessible, interoperable, and reusable (FAIR), more work is needed to lower the threshold for effective RDM not just in cardiovascular research but in all biomedical research, with data sharing and reuse being factored in at every stage of the scientific process. A culture of open science with FAIR research data should be fostered through education and training of early-career and established research professionals. Ultimately, FAIR RDM requires permanent, long-term effort at all levels. If outcomes can be shown to be superior and to promote better (and better value) science, modern RDM will make a positive difference to cardiovascular science and practice. The full position paper is available in the supplementary materials., (© 2023. The Author(s).)

Published
2024
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44. Expansion of the complex genotypic and phenotypic spectrum of FGFR2-associated neurocutaneous syndromes.

Author

Schmidt J, Kaulfuß S, Ott H, Gaubert M, Reintjes N, Bremmer F, Dreha-Kulaczewski S, Stroebel P, Yigit G, and Wollnik B

Subjects
Female, Humans, Genotype, Mutation, Missense, Receptor, Fibroblast Growth Factor, Type 2 genetics, Neurocutaneous Syndromes diagnosis, Neurocutaneous Syndromes genetics, Nevus, Sebaceous of Jadassohn genetics, Nevus, Sebaceous of Jadassohn pathology, Craniosynostoses genetics
Abstract

The fibroblast growth factor receptors comprise a family of related but individually distinct tyrosine kinase receptors. Within this family, FGFR2 is a key regulator in many biological processes, e.g., cell proliferation, tumorigenesis, metastasis, and angiogenesis. Heterozygous activating non-mosaic germline variants in FGFR2 have been linked to numerous autosomal dominantly inherited disorders including several craniosynostoses and skeletal dysplasia syndromes. We report on a girl with cutaneous nevi, ocular malformations, macrocephaly, mild developmental delay, and the initial clinical diagnosis of Schimmelpenning-Feuerstein-Mims syndrome, a very rare mosaic neurocutaneous disorder caused by postzygotic missense variants in HRAS, KRAS, and NRAS. Exome sequencing of blood and affected skin tissue identified the mosaic variant c.1647=/T > G p.(Asn549=/Lys) in FGFR2, upstream of the RAS signaling pathway. The variant is located in the tyrosine kinase domain of FGFR2 in a region that regulates the activity of the receptor and structural mapping and functional characterization revealed that it results in constitutive receptor activation. Overall, our findings indicate FGFR2-associated neurocutaneous syndrome as the accurate clinical-molecular diagnosis for the reported individual, and thereby expand the complex genotypic and phenotypic spectrum of FGFR-associated disorders. We conclude that molecular analysis of FGFR2 should be considered in the genetic workup of individuals with the clinical suspicion of a mosaic neurocutaneous condition, as the knowledge of the molecular cause might have relevant implications for genetic counseling, prognosis, tumor surveillance and potential treatment options., (© 2024. The Author(s).)

Published
2024
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45. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.

Author

Li D, Wang Q, Bayat A, Battig MR, Zhou Y, Bosch DG, van Haaften G, Granger L, Petersen AK, Pérez-Jurado LA, Aznar-Laín G, Aneja A, Hancarova M, Bendova S, Schwarz M, Kremlikova Pourova R, Sedlacek Z, Keena BA, March ME, Hou C, O'Connor N, Bhoj EJ, Harr MH, Lemire G, Boycott KM, Towne M, Li M, Tarnopolsky M, Brady L, Parker MJ, Faghfoury H, Parsley LK, Agolini E, Dentici ML, Novelli A, Wright M, Palmquist R, Lai K, Scala M, Striano P, Iacomino M, Zara F, Cooper A, Maarup TJ, Byler M, Lebel RR, Balci TB, Louie R, Lyons M, Douglas J, Nowak C, Afenjar A, Hoyer J, Keren B, Maas SM, Motazacker MM, Martinez-Agosto JA, Rabani AM, McCormick EM, Falk MJ, Ruggiero SM, Helbig I, Møller RS, Tessarollo L, Tomassoni Ardori F, Palko ME, Hsieh TC, Krawitz PM, Ganapathi M, Gelb BD, Jobanputra V, Wilson A, Greally J, Jacquemont S, Jizi K, Bruel AL, Quelin C, Misra VK, Chick E, Romano C, Greco D, Arena A, Morleo M, Nigro V, Seyama R, Uchiyama Y, Matsumoto N, Taira R, Tashiro K, Sakai Y, Yigit G, Wollnik B, Wagner M, Kutsche B, Hurst AC, Thompson ML, Schmidt R, Randolph L, Spillmann RC, Shashi V, Higginbotham EJ, Cordeiro D, Carnevale A, Costain G, Khan T, Funalot B, Tran Mau-Them F, Fernandez Garcia Moya L, García-Miñaúr S, Osmond M, Chad L, Quercia N, Carrasco D, Li C, Sanchez-Valle A, Kelley M, Nizon M, Jensson BO, Sulem P, Stefansson K, Gorokhova S, Busa T, Rio M, Hadj Habdallah H, Lesieur-Sebellin M, Amiel J, Pingault V, Mercier S, Vincent M, Philippe C, Fatus-Fauconnier C, Friend K, Halligan RK, Biswas S, Rosser J, Shoubridge C, Corbett M, Barnett C, Gecz J, Leppig K, Slavotinek A, Marcelis C, Pfundt R, de Vries BB, van Slegtenhorst MA, Brooks AS, Cogne B, Rambaud T, Tümer Z, Zackai EH, Akizu N, Song Y, and Hakonarson H

Subjects
Humans, Gene Regulatory Networks, Mutation, Missense, RNA Splicing, RNA Splicing Factors genetics, Nuclear Proteins genetics, DNA Repair Enzymes genetics, Spliceosomes genetics, Neurodevelopmental Disorders genetics
Abstract

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

Published
2024
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46. Association of Antenatal Evaluations with Postmortem and Genetic Findings in the Series of Fetal Osteogenesis Imperfecta.

Author

Senturk L, Gulec C, Sarac Sivrikoz T, Kayserili H, Kalelioglu IH, Avci S, Has R, Coucke P, Kalayci T, Wollnik B, Karaman B, Toksoy G, Symoens S, Yigit G, Yuksel A, Basaran S, Tuysuz B, Altunoglu U, and Uyguner ZO

Subjects
Humans, Female, Pregnancy, Ultrasonography, Prenatal, Collagen Type I, alpha 1 Chain, Tacrolimus Binding Proteins genetics, Male, Collagen Type I genetics, Autopsy, Prolyl Hydroxylases genetics, Adult, Membrane Glycoproteins, Membrane Proteins, Proteoglycans, Osteogenesis Imperfecta genetics, Osteogenesis Imperfecta diagnostic imaging
Abstract

Introduction: Counseling osteogenesis imperfecta (OI) pregnancies is challenging due to the wide range of onsets and clinical severities, from perinatal lethality to milder forms detected later in life., Methods: Thirty-eight individuals from 36 families were diagnosed with OI through prenatal ultrasonography and/or postmortem clinical and radiographic findings. Genetic analysis was conducted on 26 genes associated with OI in these subjects that emerged over the past 20 years; while some genes were examined progressively, all 26 genes were examined in the group where no pathogenic variations were detected., Results: Prenatal and postnatal observations both consistently showed short limbs in 97%, followed by bowing of the long bones in 89%. Among 32 evaluated cases, all exhibited cranial hypomineralization. Fractures were found in 29 (76%) cases, with multiple bones involved in 18 of them. Genetic associations were disclosed in 27 families with 22 (81%) autosomal dominant and five (19%) autosomal recessive forms, revealing 25 variants in six genes (COL1A1, COL1A2, CREB3L1, P3H1, FKBP10, and IFITM5), including nine novels. Postmortem radiological examination showed variability in intrafamily expression of CREBL3- and P3H1-related OI., Conclusion: Prenatal diagnosis for distinguishing OI and its subtypes relies on factors such as family history, timing, ultrasound, genetics, and postmortem evaluation., (© 2024 S. Karger AG, Basel.)

Published
2024
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47. Lysinuric protein intolerance caused by a homozygous SLC7A7 deletion and presented with hyperferritinemia and osteoporosis in two siblings.

Author

Kalay I, Aykut H, Caliskan Z, Yigit G, and Wollnik B

Abstract

Lysinuric protein intolerance (LPI) is a rare, inherited aminoaciduria caused by biallelic pathogenic variants in the amino acid transporter gene SLC7A7 (OMIM *603593). Individuals with LPI show extreme variability in their clinical presentation, and LPI is included in the differential diagnosis of several disorders such as urea cycle disorders, lysosomal storage diseases, malabsorption diseases, autoimmune disorders, hemochromatosis, and osteoporosis. The phenotypic variability of LPI and the lack of a specific clinical presentation have caused various misdiagnoses. Here, we report two siblings diagnosed in their 4th decade of life with LPI, manifesting rare hyperferritinemia. Additionally, they presented with short stature, multiple bone fractures due to osteoporosis, and they showed an aversion to protein-rich food. Using a combination of exome sequencing, microarray analysis and qPCR, we identified a novel homozygous deletion in SLC7A7 encompassing exons 3 to 10, which is predicted to lead to disruption of SLC7A7 function. This is the first report of lysinuric protein intolerance in a Turkish family associated with this so far unknown deletion in SLC7A7 ., Competing Interests: None., (© 2023 The Authors. Published by Elsevier Inc.)

Published
2023
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48. Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.

Author

Guo L, Salian S, Xue JY, Rath N, Rousseau J, Kim H, Ehresmann S, Moosa S, Nakagawa N, Kuroda H, Clayton-Smith J, Wang J, Wang Z, Banka S, Jackson A, Zhang YM, Wei ZJ, Hüning I, Brunet T, Ohashi H, Thomas MF, Bupp C, Miyake N, Matsumoto N, Mendoza-Londono R, Costain G, Hahn G, Di Donato N, Yigit G, Yamada T, Nishimura G, Ansel KM, Wollnik B, Hrabě de Angelis M, Mégarbané A, Rosenfeld JA, Heissmeyer V, Ikegawa S, and Campeau PM

Subjects
Humans, Mutation, Missense genetics, RNA, Ribosomal, 5.8S, RNA, RNA, Messenger genetics, Exoribonucleases genetics, Histones genetics
Abstract

ERI1 is a 3'-to-5' exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3' end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis., Competing Interests: Declaration of interests The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2023
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49. The genetic spectrum of congenital ocular motor apraxia type Cogan: an observational study, continued.

Author

Schröder S, Yigit G, Li Y, Altmüller J, Büttel HM, Fiedler B, Kretzschmar C, Nürnberg P, Seeger J, Serpieri V, Valente EM, Wollnik B, Boltshauser E, and Brockmann K

Subjects
Humans, Cerebellum abnormalities, Retina pathology, Cerebellar Diseases genetics, Eye Abnormalities genetics, Eye Abnormalities diagnosis, Eye Abnormalities pathology, Kidney Diseases, Cystic diagnosis, Kidney Diseases, Cystic genetics, Kidney Diseases, Cystic pathology
Abstract

Background: The term congenital ocular motor apraxia (COMA), coined by Cogan in 1952, designates the incapacity to initiate voluntary eye movements performing rapid gaze shift, so called saccades. While regarded as a nosological entity by some authors, there is growing evidence that COMA designates merely a neurological symptom with etiologic heterogeneity. In 2016, we reported an observational study in a cohort of 21 patients diagnosed as having COMA. Thorough re-evaluation of the neuroimaging features of these 21 subjects revealed a previously not recognized molar tooth sign (MTS) in 11 of them, thus leading to a diagnostic reassignment as Joubert syndrome (JBTS). Specific MRI features in two further individuals indicated a Poretti-Boltshauser syndrome (PTBHS) and a tubulinopathy. In eight patients, a more precise diagnosis was not achieved. We pursued this cohort aiming at clarification of the definite genetic basis of COMA in each patient., Results: Using a candidate gene approach, molecular genetic panels or exome sequencing, we detected causative molecular genetic variants in 17 of 21 patients with COMA. In nine of those 11 subjects diagnosed with JBTS due to newly recognized MTS on neuroimaging, we found pathogenic mutations in five different genes known to be associated with JBTS, including KIAA0586, NPHP1, CC2D2A, MKS1, and TMEM67. In two individuals without MTS on MRI, pathogenic variants were detected in NPHP1 and KIAA0586, arriving at a diagnosis of JBTS type 4 and 23, respectively. Three patients carried heterozygous truncating variants in SUFU, representing the first description of a newly identified forme fruste of JBTS. The clinical diagnoses of PTBHS and tubulinopathy were confirmed by detection of causative variants in LAMA1 and TUBA1A, respectively. In one patient with normal MRI, biallelic pathogenic variants in ATM indicated variant ataxia telangiectasia. Exome sequencing failed to reveal causative genetic variants in the remaining four subjects, two of them with clear MTS on MRI., Conclusions: Our findings indicate marked etiologic heterogeneity in COMA with detection of causative mutations in 81% (17/21) in our cohort and nine different genes being affected, mostly genes associated with JBTS. We provide a diagnostic algorithm for COMA., (© 2023. The Author(s).)

Published
2023
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50. Early and Midterm Outcomes of Endovascular Treatment in Arterial Manifestations of Vascular Behcet Disease.

Author

İscan HZ, Yigit G, Cetinkaya F, Erdogan K, Tumer NB, Ozen A, Mavioglu L, and Unal EU

Subjects
Male, Female, Humans, Adult, Blood Vessel Prosthesis adverse effects, Retrospective Studies, Treatment Outcome, Stents adverse effects, Postoperative Complications diagnostic imaging, Postoperative Complications etiology, Postoperative Complications therapy, Behcet Syndrome complications, Behcet Syndrome diagnosis, Blood Vessel Prosthesis Implantation, Aortic Aneurysm, Abdominal surgery, Endovascular Procedures, Aortic Aneurysm, Thoracic surgery
Abstract

Background: Behcet's disease (BD), originally described by Hulusi Behcet in 1937, is a chronic relapsing inflammatory process of an immunologic syndrome and the involvement of the vascular system is called Vasculo-Behcet disease (VBD). This is a retrospective study evaluating 21 patients diagnosed with VBD who underwent endovascular treatment., Methods: This single-center study was conducted between January 2016 and January 2022. Early and mid-term endovascular outcomes of a total of 21 patients (16 males, 5 females with a median age of 42 years; range, 31 to 46 years), with a diagnosis of VBD, who underwent endovascular arterial repair in our hospital, were retrospectively analyzed. Follow-ups were scheduled for the first and sixth postoperative months and every 6 months thereafter. For symptomatic patients, imaging studies and additional interventions were planned. The primary outcomes were a procedural success and a requirement for reintervention. Secondary outcomes were complications and all causes of mortality., Results: Twenty-one patients underwent endovascular repair. In this study, 1 balloon-expandable stent for brachial artery aneurysm (4,8%), 1 viabahn graft for femoral artery aneurysm (4,8%), 2 tube endograft for ruptured iliac artery aneurysm (9,5%), 1 tube endograft (Thoracic endovascular aortic repair [TEVAR]) insertion at the aortic bifurcation for infrarenal abdominal aortic occlusion (4,8%), 1 chimney-TEVAR for saccular arcus thoracic aortic aneurysm (TAA) (4,8%) and 7 TEVAR for saccular TAA (33,3%), 1 EVAR for an intact and symptomatic infrarenal abdominal aortic aneurysm (AAA) (4,8%), 1 EVAR (aorto-uniiliac) for ruptured iliac artery aneurysm (4,8%), and 6 EVAR for ruptured AAA (28,5%) were deployed. The technical success rate was 100% with a mean follow-up period of 50. 4 ± 10.7 months (8-66 months). The mean aneurysm diameter was 10,7 ± 53 mm. In the follow-up period, 3 patients presented with a hematoma at the insertion site of the sheath (14.3%). There were no early mortalities. Three patients required reintervention (14,3%); 1 of these underwent open surgical repair due to a pseudoaneurysm of the access site (4,8%). The Kaplan-Meier analysis revealed freedom from reintervention rate as 94,1 ± 5,7% at 1 year, 85,6 ± 9,7% at 3 years, and 68,4 ± 17,1% at 5 years., Conclusions: Awareness of the BD especially for vascular involvements in young ages is lifesaving. Endovascular therapy with proper medical treatment seems to be the treatment of choice according to the early and midterm successful results with low morbidity and mortality., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Published
2023
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