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4. Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase

Author

Jones, Amy G., Aquilino, Matilde, Tinker, Rory J., Duncan, Laura, Jenkins, Zandra, Carvill, Gemma L., DeWard, Stephanie J., Grange, Dorothy K., Hajianpour, MJ, Halliday, Benjamin J., Holder-Espinasse, Muriel, Horvath, Judit, Maitz, Silvia, Nigro, Vincenzo, Morleo, Manuela, Paul, Victoria, Spencer, Careni, Esterhuizen, Alina I., Polster, Tilman, Spano, Alice, Gómez-Lozano, Inés, Kumar, Abhishek, Poke, Gemma, Phillips, John A., III, Underhill, Hunter R., Gimenez, Gregory, Namba, Takashi, and Robertson, Stephen P.

Published
2024
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5. Population‐based prevalence of congenital defects in a routine sentinel site‐based surveillance system in the Western Cape, South Africa.

Author

Kalk, Emma, Heekes, Alexa, Lavies, Diane, Jacobs, Lizel, Spencer, Careni, Boutall, Alison, Osman, Ayesha, Stewart, Chantal, Davies, Mary‐Ann, van Niekerk, Anika, Fieggen, Karen, Boulle, Andrew, and Mehta, Ushma

Abstract

Background: Lack of data on the burden and scope of congenital disorders (CDs) in South Africa undermines resource allocation and limits the ability to detect signals from potentially teratogenic pregnancy exposures. Methods: We used routine electronic data in the Western Cape Pregnancy Exposure Registry (PER) to determine the overall and individual prevalence of CD identified on neonatal surface examination at birth in the Western Cape, South Africa, 2016–2022. CD was confirmed by record review. The contribution of late (≤24 months) and antenatal diagnoses was assessed. We compared demographic and obstetric characteristics between women with/without pregnancies affected by CD. Results: Women with a viable pregnancy (>22 weeks gestation; birth weight ≥ 500 g) (n = 32,494) were included. Of 1106 potential CD identified, 56.1% were confirmed on folder review. When internal and minor CD were excluded the prevalence of major CD identified on surface examination at birth was 7.2/1000 births. When missed/late diagnoses on examination (16.8%) and ultrasound (6.8%) were included, the prevalence was 9.2/1000 births: 8.9/1000 livebirths and 21.5/1000 stillbirths. The PER did not detect 21.5% of major CD visible at birth. Older maternal age and diabetes mellitus were associated with an increased prevalence of CD. Women living with/without HIV (or the timing of antiretroviral therapy, before/after conception), hypertension or obesity did not significantly affect prevalence of CD. Conclusions: A surveillance system based on routine data successfully determined the prevalence of major CD identified on surface examination at birth at rates slightly higher than in equivalent studies. Overall rates, modeled at ~2%, are likely underestimated. Strengthening routine neonatal examination and clinical record‐keeping could improve CD ascertainment. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Clinical, biochemical, and genetic spectrum of MADD in a South African cohort: an ICGNMD study

Author

Bisschoff, Michelle, primary, Smuts, Izelle, additional, Dercksen, Marli, additional, Schoonen, Maryke, additional, Vorster, Barend Christiaan, additional, Watt, George van der, additional, Spencer, Careni, additional, Naidu, Kireshnee, additional, Henning, Franclo, additional, Meldau, Surita, additional, McFarland, Robert, additional, Taylor, Robert, additional, Patel, Krutik, additional, Fassad, Mahmoud R, additional, Vandrovcova, Jana, additional, Consortium, The ICGNMD, additional, Wanders, Ronald JA, additional, and Westhuizen, Francois Hendrikus van der, additional

Published
2023
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8. Mutation profiling in South African patients with Cornelia de Lange syndrome phenotype.

Author

Seymour, Heather, Feben, Candice, Nevondwe, Patracia, Kerr, Robyn, Spencer, Careni, Mudau, Maria, Honey, Engela, Lombard, Zane, Krause, Amanda, and Carstens, Nadia

Subjects
SOUTH Africans, NUCLEOTIDE sequencing, GENETIC variation, GENETIC mutation, AFRICANS, PHENOTYPES, EXOMES
Abstract

Background: Cornelia de Lange Syndrome (CdLS) presents with a variable multi‐systemic phenotype and pathogenic variants have been identified in five main genes. This condition has been understudied in African populations with little phenotypic and molecular information available. Methods and Results: We present a cohort of 14 patients with clinical features suggestive of CdLS. Clinical phenotyping was carried out and cases were classified according to the international consensus criteria. According to this criteria, nine patients had classical CdLS, one had non‐classical CdLS and four presented with a phenotype that suggested molecular testing for CdLS. Each patient underwent mutation profiling using a targeted next generation sequencing panel of 18 genes comprising known and suspected CdLS causal genes. Of the 14 patients tested, pathogenic and likely pathogenic variants were identified in nine: eight variants in the NIPBL gene and one in the STAG1 gene. Conclusions: We present the first molecular data for a cohort of South African patients with CdLS. Eight of the nine variants identified were in the NIPBL gene, the most commonly involved gene in cases of CdLS. This is also the first report of a patient of African ancestry presenting with STAG1‐related CdLS. [ABSTRACT FROM AUTHOR]

Published
2024
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13. SCN3A‐Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation

Author

Zaman, Tariq, primary, Helbig, Katherine L., additional, Clatot, Jérôme, additional, Thompson, Christopher H., additional, Kang, Seok Kyu, additional, Stouffs, Katrien, additional, Jansen, Anna E., additional, Verstraete, Lieve, additional, Jacquinet, Adeline, additional, Parrini, Elena, additional, Guerrini, Renzo, additional, Fujiwara, Yuh, additional, Miyatake, Satoko, additional, Ben‐Zeev, Bruria, additional, Bassan, Haim, additional, Reish, Orit, additional, Marom, Daphna, additional, Hauser, Natalie, additional, Vu, Thuy‐Anh, additional, Ackermann, Sally, additional, Spencer, Careni E., additional, Lippa, Natalie, additional, Srinivasan, Shraddha, additional, Charzewska, Agnieszka, additional, Hoffman‐Zacharska, Dorota, additional, Fitzpatrick, David, additional, Harrison, Victoria, additional, Vasudevan, Pradeep, additional, Joss, Shelagh, additional, Pilz, Daniela T., additional, Fawcett, Katherine A., additional, Helbig, Ingo, additional, Matsumoto, Naomichi, additional, Kearney, Jennifer A., additional, Fry, Andrew E., additional, and Goldberg, Ethan M., additional

Published
2020
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15. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Acuna-Hidalgo, Rocio, primary, Deriziotis, Pelagia, additional, Steehouwer, Marloes, additional, Gilissen, Christian, additional, Graham, Sarah A., additional, van Dam, Sipko, additional, Hoover-Fong, Julie, additional, Telegrafi, Aida B., additional, Destree, Anne, additional, Smigiel, Robert, additional, Lambie, Lindsday A., additional, Kayserili, Hülya, additional, Altunoglu, Umut, additional, Lapi, Elisabetta, additional, Uzielli, Maria Luisa, additional, Aracena, Mariana, additional, Nur, Banu G., additional, Mihci, Ercan, additional, Moreira, Lilia M. A., additional, Borges Ferreira, Viviane, additional, Horovitz, Dafne D. G., additional, da Rocha, Katia M., additional, Jezela-Stanek, Aleksandra, additional, Brooks, Alice S., additional, Reutter, Heiko, additional, Cohen, Julie S., additional, Fatemi, Ali, additional, Smitka, Martin, additional, Grebe, Theresa A., additional, Di Donato, Nataliya, additional, Deshpande, Charu, additional, Vandersteen, Anthony, additional, Marques Lourenço, Charles, additional, Dufke, Andreas, additional, Rossier, Eva, additional, Andre, Gwenaelle, additional, Baumer, Alessandra, additional, Spencer, Careni, additional, McGaughran, Julie, additional, Franke, Lude, additional, Veltman, Joris A., additional, De Vries, Bert B. A., additional, Schinzel, Albert, additional, Fisher, Simon E., additional, Hoischen, Alexander, additional, and van Bon, Bregje W., additional

Published
2017
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18. Implications of direct-to-consumer whole-exome sequencing in South Africa

Author

Lombard, Zané, primary, Baine, Fiona, additional, Krause, Amanda, additional, Lochan, Anneline, additional, Macualay, Shelley, additional, Spencer, Careni, additional, Aldous, Colleen, additional, De Vries, Jantina, additional, Fieggen, Karen, additional, Henderson, Bertram, additional, Hoal, Eileen, additional, Kinnear, Craig, additional, Kinsley, Noelene, additional, September, Alison, additional, Urban, Michael, additional, Soodyall, Himla, additional, Pepper, Michael, additional, and Ramsay, Michele, additional

Published
2016
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19. The characterization of Lowe Syndrome in a South African cohort

Author

Sulaiman-Baradien, Rizqa, Spencer, Careni, and Agenbag, Gloudi

Subjects
Clinical Laboratory Sciences
Abstract

Oculocerebrorenal or Lowe Syndrome (OMIM #309000) is an X-linked recessive condition characterized by a triad of congenital cataracts, proximal renal tubular dysfunction, and variable central nervous system involvement. Nearly all affected boys will be hemizygous for a pathogenic variant in the OCRL (NM_000276.4 c.2615delC) gene. We present a clinical and molecular characterization of an extended multiplex family of three affected boys with Lowe Syndrome and describe a novel variant, predicted to be pathogenic, in the OCRL gene. This is to the best of our knowledge the first description of its kind in South African patients and future research into more families with Lowe syndrome will be beneficial.

Published
2020

20. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Lilia Maria de Azevedo Moreira, Joris A. Veltman, Anne Destree, Ercan Mihci, Banu Güzel Nur, Charles Marques Lourenço, Eva Rossier, Simon E. Fisher, Julie S. Cohen, Julie Hoover-Fong, Viviane Borges Ferreira, Mariana Aracena, Aida Telegrafi, Kátia Maria da Rocha, Alexander Hoischen, Julie McGaughran, Hülya Kayserili, Anthony Vandersteen, Lindsday A. Lambie, Bert B.A. de Vries, Sarah A. Graham, Heiko Reutter, Alessandra Baumer, Pelagia Deriziotis, Andreas Dufke, Maria Luisa Giovannucci Uzielli, Robert Smigiel, Theresa A. Grebe, Albert Schinzel, Christian Gilissen, Bregje W.M. van Bon, Careni Spencer, Marloes Steehouwer, Martin Smitka, Alice S. Brooks, Umut Altunoglu, Elisabetta Lapi, Charu Deshpande, Aleksandra Jezela-Stanek, Dafne Dain Gandelman Horovitz, Nataliya Di Donato, Ali Fatemi, Gwenaelle Andre, Lude Franke, Rocio Acuna-Hidalgo, Sipko van Dam, Clinical Genetics, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Acuna-Hidalgo, Rocio, Deriziotis, Pelagia, Steehouwer, Marloes, Gilissen, Christian, Graham, Sarah, Dam, Sipko van, Hoover-Fong, Julie, Telegrafi, Aida, Destree, Anne, Smigiel, Robert, Lambie, Lindsday, Altunoglu, Umut, Lapi, Elisabetta, Uzielli, Maria Luisa, Aracena, Mariana, Nur, Banu G., Mihci, Ercan, Moreira, Lilia M. A., Borges Ferreira, Viviane, Horovitz, Dafne D. G., Rocha, Katia M. da, Jezela-Stanek, Aleksandra, Brooks, Alice S., Reutter, Heiko, Cohen, Julie S., Fatemi, Ali, Smitka, Martin, Grebe, Theresa A., Donato, Nataliya Di, Deshpande, Charu, Vandersteen, Anthony, Lourenço, Charles Marques, Dufke, Andreas, Rossier, Eva, Andre, Gwenaelle, Baumer, Alessandra, Spencer, Careni, McGaughran, Julie, Franke, Lude, Veltman, Joris A., Vries, Bert B. A. de, Schinzel, Albert, Fisher, Simon E., Hoischen, Alexander, Bon, Bregje W. van, School of Medicine, Department of Genetics, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
0301 basic medicine, Male, Cancer Research, Somatic cell, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Gene Identification and Analysis, Gene Expression, medicine.disease_cause, Biochemistry, Germline, Hematologic Cancers and Related Disorders, Craniofacial Abnormalities, Exon, Database and Informatics Methods, Animal Cells, Medicine and Health Sciences, Nuclear protein, Child, Genetics (clinical), ATYPICAL CML, MYELODYSPLASTIC SYNDROME, Connective Tissue Cells, Genetics, Medicine, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], CLONAL HEMATOPOIESIS, Hematology, CHRONIC NEUTROPHILIC LEUKEMIA, Germline Mutation, Phenotype, 3. Good health, Cell Transformation, Neoplastic, Oncology, Connective Tissue, Child, Preschool, Hematologic Neoplasms, Female, Cellular Types, Anatomy, Neurodevelopmental disorders Radboud Institute for Molecular Life Sciences [Radboudumc 7], Hand Deformities, Congenital, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Research Article, Neuroinformatics, lcsh:QH426-470, Blotting, Western, Nails, Malformed, Protein degradation, Biology, Research and Analysis Methods, Cell Line, PROGRESSIVE BRAIN ATROPHY, 03 medical and health sciences, Germline mutation, Intellectual Disability, Leukemias, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, JUVENILE MYELOMONOCYTIC LEUKEMIA, CHRONIC MYELOID-LEUKEMIA, Protein Interactions, Molecular Biology, Mutation Detection, Ecology, Evolution, Behavior and Systematics, Genetic Association Studies, Germ-Line Mutation, Cell Proliferation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CHILDHOOD-CANCER, Gene Expression Profiling, DISEASE PROGRESSION, Infant, Newborn, Biology and Life Sciences, Cancers and Neoplasms, Proteins, Infant, CSF3R T618I, Cell Biology, Fibroblasts, Chronic neutrophilic leukemia, Chronic myeloid-leukemia, Juvenile myelomonocytic leukemia, Progressive brain atrophy, Myelodysplastic syndrome, Clonal hematopoiesis, Disease progression, Childhood-cancer, Atypical cml, Csf3r T618i, lcsh:Genetics, 030104 developmental biology, Biological Tissue, Biological Databases, HEK293 Cells, Mutation, Mutation Databases, Cancer research, Somatic Mutation, Carcinogenesis, Carrier Proteins
Abstract

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients ( including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype., Radboud University Medical Center; Max Planck Society; European Research Council (ERC); VIDI; Netherlands Organization for Scientific Research (NWO); Netherlands Organization for Scientific Research

Published
2017

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