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1. Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease

Author

Yask Gupta, David J. Friedman, Michelle T. McNulty, Atlas Khan, Brandon Lane, Chen Wang, Juntao Ke, Gina Jin, Benjamin Wooden, Andrea L. Knob, Tze Y. Lim, Gerald B. Appel, Kinsie Huggins, Lili Liu, Adele Mitrotti, Megan C. Stangl, Andrew Bomback, Rik Westland, Monica Bodria, Maddalena Marasa, Ning Shang, David J. Cohen, Russell J. Crew, William Morello, Pietro Canetta, Jai Radhakrishnan, Jeremiah Martino, Qingxue Liu, Wendy K. Chung, Angelica Espinoza, Yuan Luo, Wei-Qi Wei, Qiping Feng, Chunhua Weng, Yilu Fang, Iftikhar J. Kullo, Mohammadreza Naderian, Nita Limdi, Marguerite R. Irvin, Hemant Tiwari, Sumit Mohan, Maya Rao, Geoffrey K. Dube, Ninad S. Chaudhary, Orlando M. Gutiérrez, Suzanne E. Judd, Mary Cushman, Leslie A. Lange, Ethan M. Lange, Daniel L. Bivona, Miguel Verbitsky, Cheryl A. Winkler, Jeffrey B. Kopp, Dominick Santoriello, Ibrahim Batal, Sérgio Veloso Brant Pinheiro, Eduardo Araújo Oliveira, Ana Cristina Simoes e Silva, Isabella Pisani, Enrico Fiaccadori, Fangming Lin, Loreto Gesualdo, Antonio Amoroso, Gian Marco Ghiggeri, Vivette D. D’Agati, Riccardo Magistroni, Eimear E. Kenny, Ruth J. F. Loos, Giovanni Montini, Friedhelm Hildebrandt, Dirk S. Paul, Slavé Petrovski, David B. Goldstein, Matthias Kretzler, Rasheed Gbadegesin, Ali G. Gharavi, Krzysztof Kiryluk, Matthew G. Sampson, Martin R. Pollak, and Simone Sanna-Cherchi

Subjects
Science
Abstract

Abstract African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.

Published
2023
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2. Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome

Author

Alexandra Barry, Michelle T. McNulty, Xiaoyuan Jia, Yask Gupta, Hanna Debiec, Yang Luo, China Nagano, Tomoko Horinouchi, Seulgi Jung, Manuela Colucci, Dina F. Ahram, Adele Mitrotti, Aditi Sinha, Nynke Teeninga, Gina Jin, Shirlee Shril, Gianluca Caridi, Monica Bodria, Tze Y. Lim, Rik Westland, Francesca Zanoni, Maddalena Marasa, Daniel Turudic, Mario Giordano, Loreto Gesualdo, Riccardo Magistroni, Isabella Pisani, Enrico Fiaccadori, Jana Reiterova, Silvio Maringhini, William Morello, Giovanni Montini, Patricia L. Weng, Francesco Scolari, Marijan Saraga, Velibor Tasic, Domenica Santoro, Joanna A. E. van Wijk, Danko Milošević, Yosuke Kawai, Krzysztof Kiryluk, Martin R. Pollak, Ali Gharavi, Fangmin Lin, Ana Cristina Simœs e Silva, Ruth J. F. Loos, Eimear E. Kenny, Michiel F. Schreuder, Aleksandra Zurowska, Claire Dossier, Gema Ariceta, Magdalena Drozynska-Duklas, Julien Hogan, Augustina Jankauskiene, Friedhelm Hildebrandt, Larisa Prikhodina, Kyuyoung Song, Arvind Bagga, Hae Cheong, Gian Marco Ghiggeri, Prayong Vachvanichsanong, Kandai Nozu, Dongwon Lee, Marina Vivarelli, Soumya Raychaudhuri, Katsushi Tokunaga, Simone Sanna-Cherchi, Pierre Ronco, Kazumoto Iijima, and Matthew G. Sampson

Subjects
Science
Abstract

Abstract Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations—eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.

Published
2023
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3. Copy Number Variation Analysis Facilitates Identification of Genetic Causation in Patients with Congenital Anomalies of the Kidney and Urinary Tract

Author

Chen-Han Wilfred Wu, Tze Y. Lim, Chunyan Wang, Steve Seltzsam, Bixia Zheng, Luca Schierbaum, Sophia Schneider, Nina Mann, Dervla M. Connaughton, Makiko Nakayama, Amelie T. van der Ven, Rufeng Dai, Caroline M. Kolvenbach, Franziska Kause, Isabel Ottlewski, Natasa Stajic, Neveen A. Soliman, Jameela A. Kari, Sherif El Desoky, Hanan M. Fathy, Danko Milosevic, Daniel Turudic, Muna Al Saffar, Hazem S. Awad, Loai A. Eid, Aravind Ramanathan, Prabha Senguttuvan, Shrikant M. Mane, Richard S. Lee, Stuart B. Bauer, Weining Lu, Alina C. Hilger, Velibor Tasic, Shirlee Shril, Simone Sanna-Cherchi, and Friedhelm Hildebrandt

Subjects
Congenital anomalies of the kidney and urinary tract, Vesicoureteral reflux, Copy number variation, Whole-exome sequencing, Monogenic disease causation, Renal developmental, Diseases of the genitourinary system. Urology, RC870-923, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease among children and adults younger than 30 yr. In our previous study, whole-exome sequencing (WES) identified a known monogenic cause of isolated or syndromic CAKUT in 13% of families with CAKUT. However, WES has limitations and detection of copy number variations (CNV) is technically challenging, and CNVs causative of CAKUT have previously been detected in up to 16% of cases. Objective: To detect CNVs causing CAKUT in this WES cohort and increase the diagnostic yield. Design, setting, and participants: We performed a genome-wide single nucleotide polymorphism (SNP)-based CNV analysis on the same CAKUT cohort for whom WES was previously conducted. Outcome measurements and statistical analysis: We evaluated and classified the CNVs using previously published predefined criteria. Results and limitations: In a cohort of 170 CAKUT families, we detected a pathogenic CNV known to cause CAKUT in nine families (5.29%, 9/170). There were no competing variants on genome-wide CNV analysis or WES analysis. In addition, we identified novel likely pathogenic CNVs that may cause a CAKUT phenotype in three of the 170 families (1.76%). Conclusions: CNV analysis in this cohort of 170 CAKUT families previously examined via WES increased the rate of diagnosis of genetic causes of CAKUT from 13% on WES to 18% on WES + CNV analysis combined. We also identified three candidate loci that may potentially cause CAKUT. Patient summary: We conducted a genetics study on families with congenital anomalies of the kidney and urinary tract (CAKUT). We identified gene mutations that can explain CAKUT symptoms in 5.29% of the families, which increased the percentage of genetic causes of CAKUT to 18% from a previous study, so roughly one in five of our patients with CAKUT had a genetic cause. These analyses can help patients with CAKUT and their families in identifying a possible genetic cause.

Published
2022
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4. CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Author

Charlotte Gehin, Museer A. Lone, Winston Lee, Laura Capolupo, Sylvia Ho, Adekemi M. Adeyemi, Erica H. Gerkes, Alexander P.A. Stegmann, Estrella López-Martín, Eva Bermejo-Sánchez, Beatriz Martínez-Delgado, Christiane Zweier, Cornelia Kraus, Bernt Popp, Vincent Strehlow, Daniel Gräfe, Ina Knerr, Eppie R. Jones, Stefano Zamuner, Luciano A. Abriata, Vidya Kunnathully, Brandon E. Moeller, Anthony Vocat, Samuel Rommelaere, Jean-Philippe Bocquete, Evelyne Ruchti, Greta Limoni, Marine Van Campenhoudt, Samuel Bourgeat, Petra Henklein, Christian Gilissen, Bregje W. van Bon, Rolph Pfundt, Marjolein H. Willemsen, Jolanda H. Schieving, Emanuela Leonardi, Fiorenza Soli, Alessandra Murgia, Hui Guo, Qiumeng Zhang, Kun Xia, Christina R. Fagerberg, Christoph P. Beier, Martin J. Larsen, Irene Valenzuela, Paula Fernández-Álvarez, Shiyi Xiong, Robert Śmigiel, Vanesa López-González, Lluís Armengol, Manuela Morleo, Angelo Selicorni, Annalaura Torella, Moira Blyth, Nicola S. Cooper, Valerie Wilson, Renske Oegema, Yvan Herenger, Aurore Garde, Ange-Line Bruel, Frederic Tran Mau-Them, Alexis B.R. Maddocks, Jennifer M. Bain, Musadiq A. Bhat, Gregory Costain, Peter Kannu, Ashish Marwaha, Neena L. Champaigne, Michael J. Friez, Ellen B. Richardson, Vykuntaraju K. Gowda, Varunvenkat M. Srinivasan, Yask Gupta, Tze Y. Lim, Simone Sanna-Cherchi, Bruno Lemaitre, Toshiyuki Yamaji, Kentaro Hanada, John E. Burke, Ana Marjia Jakšić, Brian D. McCabe, Paolo De Los Rios, Thorsten Hornemann, Giovanni D’Angelo, and Vincenzo A. Gennarino

Subjects
Cell biology, Genetics, Medicine
Abstract

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.

Published
2023
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6. Multi-population genome-wide association study implicates both immune and non-immune factors in the etiology of pediatric steroid sensitive nephrotic syndrome

Author

Alexandra Barry, Michelle T. McNulty, Xiaoyuan Jia, Yask Gupta, Hanna Debiec, Yang Luo, China Nagano, Tomoko Horinouchi, Seulgi Jung, Manuela Colucci, Dina F. Ahram, Adele Mitrotti, Aditi Sinha, Nynke Teeninga, Gina Jin, Shirlee Shril, Gianluca Caridi, Monica Bodria, Tze Y Lim, Rik Westland, Francesca Zanoni, Maddalena Marasa, Daniel Turudic, Mario Giordano, Loreto Gesualdo, Riccardo Magistroni, Isabella Pisani, Enrico Fiaccadori, Jana Reiterova, Silvio Maringhini, William Morello, Giovanni Montini, Patricia L. Weng, Francesco Scolari, Marijan Saraga, Velibor Tasic, Domenica Santoro, Joanna A.E. van Wijk, Danko Milošević, Yosuke Kawai, Krzysztof Kiryluk, Martin R. Pollak, Ali Gharavi, Fangmin Lin, Ana Cristina Simœs e Silva, Ruth J.F. Loos, Eimear E. Kenny, Michiel F. Schreuder, Aleksandra Zurowska, Claire Dossier, Gema Ariceta, Magdalena Drozynska-Duklas, Julien Hogan, Augustina Jankauskiene, Friedhelm Hildebrandt, Larisa Prikhodina, Kyuyoung Song, Arvind Bagga, Hae Il Cheong, Gian Marco Ghiggeri, Prayong Vachvanichsanong, Kandai Nozu, Marina Vivarelli, Soumya Raychaudhuri, Katsushi Tokunaga, Simone Sanna-Cherchi, Pierre Ronco, Kazumoto Iijima, and Matthew G. Sampson

Abstract

Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional signals. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. We conducted a multi-population GWAS meta-analysis in 38,463 participants (2,440 cases) and population specific GWAS, discovering twelve significant associations (eight novel). Fine-mapping implicated specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk signal. Non-HLA loci colocalized with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs was lacking, but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associated with earlier disease onset in two independent cohorts. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cellspecific insights into its molecular drivers.

Published
2022

7. Genomic Disorders in CKD across the Lifespan

Author

Miguel Verbitsky, Sarathbabu Krishnamurthy, Priya Krithivasan, Daniel Hughes, Atlas Khan, Maddalena Marasà, Natalie Vena, Pavan Khosla, Junying Zhang, Tze Y. Lim, Joseph T. Glessner, Chunhua Weng, Ning Shang, Yufeng Shen, George Hripcsak, Hakon Hakonarson, Iuliana Ionita-Laza, Brynn Levy, Eimear E. Kenny, Ruth J.F. Loos, Krzysztof Kiryluk, Simone Sanna-Cherchi, David R. Crosslin, Susan Furth, Bradley A. Warady, Robert P. Igo, Sudha K. Iyengar, Craig S. Wong, Afshin Parsa, Harold I. Feldman, and Ali G. Gharavi

Subjects
Nephrology, General Medicine
Abstract

Genomic disorders (GDs) are associated with many comorbid outcomes, including CKD. Identification of GDs has diagnostic utility.We examined the prevalence of GDs among participants in the Chronic Kidney Disease in Children (CKiD) cohort II (We found nine out of 248 (3.6%) CKiD II participants carried a GD, replicating prior findings in pediatric CKD. We also identified GDs in 72 out of 6679 (1.1%) adult patients with CKD in the CRIC, CU-CKD, and FIND cohorts, compared with 199 out of 30,746 (0.65%) GDs in controls (OR, 1.7; 95% CI, 1.3 to 2.2). Among adults with CKD, we found recurrent GDs at the 1q21.1, 16p11.2, 17q12, and 22q11.2 loci. The 17q12 GD (diagnostic of renal cyst and diabetes syndrome) was most frequent, present in 1:252 patients with CKD and diabetes. In the PheWAS, dialysis and neuropsychiatric phenotypes were the top associations with GDs. In CRIC participants, GDs were associated with lower serum magnesium, lower educational achievement, and higher mortality risk.Undiagnosed GDs are detected both in children and adults with CKD. Identification of GDs in these patients can enable a precise genetic diagnosis, inform prognosis, and help stratify risk in clinical studies. GDs could also provide a molecular explanation for nephropathy and comorbidities, such as poorer neurocognition for a subset of patients.

Published
2022

8. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

Author

Verena Klämbt, Youying Mao, Vimla Aggarwal, Arang Kim, Friedhelm Hildebrandt, Mohamad A. Mikati, Vandana Shashi, Anne H. O’Donnell-Luria, Vaidehi Jobanputra, Jeremiah Martino, Vivette D. D'Agati, Minxian Wang, Marcus R. Benz, Shoji Yano, Janine Altmüller, Ali G. Gharavi, Florian Buerger, Enrico Fiaccadori, Richard P. Lifton, Bodo B. Beck, Amy Kolb, Mordi Muorah, David Goldstein, Nina Mann, Martin R. Pollak, Dina Ahram, Heidi Cope, Gian Marco Ghiggeri, Jillian S. Parboosingh, Asmaa S. AbuMaziad, Kamal Khan, Ana C. Onuchic-Whitford, Louise Bier, Emma Pierce-Hoffman, Jonathan E. Zuckerman, Shrikant Mane, Moin A. Saleem, Amar J. Majmundar, Heidi L. Rehm, Ora Yadin, Erin L. Heinzen, Gina Y. Jin, Christelle Moufawad El Achkar, Konstantin Deutsch, Julia Hoefele, Ania Koziell, Gianluca Caridi, Talha Gunduz, Agnieszka Bierzynska, Korbinian M. Riedhammer, Monica Bodria, Ronen Schneider, Julian A. Martinez-Agosto, Thomas M. Kitzler, Shirlee Shril, Ulrike John-Kroegel, Howard Trachtman, Adele Mitrotti, Eleanor G. Seaby, Amanda V. Tyndall, Isabella Pisani, Patricia L. Weng, Tze Y Lim, A. Micheil Innes, John Musgrove, Simone Sanna-Cherchi, and Erica E. Davis

Subjects
Adult, Male, 0301 basic medicine, Proband, medicine.medical_specialty, Nephrotic Syndrome, Developmental Disabilities, 030232 urology & nephrology, Neurogenetics, Nerve Tissue Proteins, Biology, Kidney, Cell Line, Mice, 03 medical and health sciences, Exon, 0302 clinical medicine, Focal segmental glomerulosclerosis, Report, Exome Sequencing, Genetics, medicine, Animals, Humans, Child, Exome, Genetics (clinical), Exome sequencing, Epilepsy, Glomerulosclerosis, Focal Segmental, Podocytes, medicine.disease, 3. Good health, Phenotype, 030104 developmental biology, Codon, Nonsense, Child, Preschool, Mutation, Medical genetics, Female, Intranuclear Space, Carrier Proteins, Nephrotic syndrome
Abstract

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10(−11)). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10(−15)). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Published
2021

9. Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations

Author

Danielle J. Owen, David FitzPatrick, Nina Mann, Stuart B. Bauer, Ilona Krey, Heather C Mefford, Jacob Zyskind, Roger Fick, Ana C. Onuchic-Whitford, Floor A. M. Duijkers, Etienne Coyaud, Simon E. Fisher, Juliann M. Savatt, Richard P. Lifton, Isabel Ottlewski, Amelie T. van der Ven, Peter J. Hulick, Nancy Rodig, Michelle A. Baum, Marielle Alders, Elysa J. Marco, Konrad Platzer, Ghaleb Daouk, Hadas Ityel, Eva H. Brilstra, Ian A. Glass, Heiko Reutter, Adda L. Graham-Paquin, Makiko Nakayama, Michael A. J. Ferguson, Amy Kolb, Weining Lu, Florian Buerger, Prabha Senguttuvan, Marcia Ferguson, Ronen Schneider, Isabelle Thiffault, Hila Milo Rasouly, Verena Klämbt, Tobias Bartolomaeus, Evan Chen, Mao Youying, Amar J. Majmundar, Jia Rao, Carrie Costin, Dina Ahram, Ali G. Gharavi, Lot Snijders Blok, Avram Z. Traum, Franziska Kause, Konstantin Deutsch, Arianna Vino, Dervla M. Connaughton, Antonie D. Kline, Deborah R. Stein, Daanya Salmanullah, Maxime Bouchard, Estelle M.N. Laurent, Audrey Squire, Daniel G. MacArthur, Kristen M. Laricchia, Asaf Vivante, Thomas M. Kitzler, Jonathan St-Germain, Brian Raught, Heidi L. Rehm, Ellen van Binsbergen, Chen Han Wilfred Wu, Caroline M. Kolvenbach, Monkol Lek, Selvin Kumar, Jing Chen, Mustafa K. Khokha, Ankana Daga, Hong Xu, Andrew D. Sharrocks, N. V. Shcherbakova, Simone Sanna-Cherchi, Inna S. Povolotskaya, Tze Y Lim, Johanna M. Rieke, Katrina M. Dipple, Gabriel C. Dworschak, Michael J. Somers, Tobias Hermle, Stefan Kohl, Steve Seltzsam, Victoria Y. Voinova, Shirlee Shril, Ingrid M. Wentzensen, Daw Yang Hwang, Velibor Tasic, Shrikant Mane, Jonathan Marquez, Friedhelm Hildebrandt, Rufeng Dai, Paulien A Terhal, Loai A. Eid, Thomas D. Challman, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), University of Western Ontario (UWO), Fudan University [Shanghai], University of Manchester [Manchester], Yale University [New Haven], McGill University = Université McGill [Montréal, Canada], Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Health Network, University of Toronto, Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Radboud University Medical Center [Nijmegen], Brigham & Women’s Hospital [Boston] (BWH), Tel Aviv University (TAU), University of Amsterdam [Amsterdam] (UvA), Universität Leipzig, University Medical Center [Utrecht], Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), GeneDx [Gaithersburg, MD, USA], University of Akron, University of Washington [Seattle], William Harvey Research Institute, Barts and the London Medical School, University of Edinburgh, Mary Bridge Childrens Hospital [Tacoma, WA, USA], NorthShore University HealthSystem [Evanston, IL, USA], Institute of Child Health [Tamil Nadu, India] (Hospital for Children), Boston University [Boston] (BU), Cortica Healthcare [San Rafael, CA, USA], Moscow Medical Institute of Health Ministry [Moscow, Russia], Pirogov Russian National Research Medical University, Dr. Mehta's Hospitals [Tamil Nadu, India], Seattle Children’s Hospital, Children's Mercy Hospital [Kansas City], University of Missouri [Kansas City] (UMKC), University of Missouri System, Neuro Spinal Hospital [Dubai, UAE], University Children’s Hospital [Skopje, Macédoine], Columbia University [New York], University Hospital Bonn, Massachusetts General Hospital [Boston], Rockefeller University [New York], Yale School of Medicine [New Haven, Connecticut] (YSM), Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Radboud university [Nijmegen], Tel Aviv University [Tel Aviv], Universität Leipzig [Leipzig], Pirogov Russian National Research Medical University [Moscow, Russia], Yale University School of Medicine, INSERM, Université de Lille, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192, and SALZET, Michel

Subjects
0301 basic medicine, Male, Morpholino, Xenopus, 030232 urology & nephrology, Endogenous retrovirus, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], transcription regulator, Interactome, Epigenesis, Genetic, Morpholinos, Pathogenesis, ZNF198, Mice, 0302 clinical medicine, whole-exome sequencing, Child, Urinary Tract, Genetics (clinical), Exome sequencing, Genetics, Mice, Knockout, ZMYM2, genetic kidney disease, Forkhead Transcription Factors, FOXP1, 3. Good health, Pedigree, extra-renal features, DNA-Binding Proteins, Child, Preschool, Larva, syndromic CAKUT, Female, Protein Binding, Neuroinformatics, Heterozygote, Biology, Article, Amphibian Proteins, 03 medical and health sciences, Exome Sequencing, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Gene silencing, Animals, Humans, Family, Transcription factor, FIM, Infant, Repressor Proteins, 030104 developmental biology, genomic analysis, Case-Control Studies, Urogenital Abnormalities, congenital anomalies of the kidney and urinary tract, Mutation, Transcription Factors
Abstract

International audience; Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CA-KUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpho-lino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and cranio-facial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endoge-nous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

Published
2020

10. The copy number variation landscape of congenital anomalies of the kidney and urinary tract

Author

Adele Mitrotti, David Fasel, Nan Wu, Joanna A.E. van Wijk, Monica Bodria, Jeremiah Martino, Alejandra Perez, Marcin Tkaczyk, Loreto Gesualdo, Katarzyna Zachwieja, Marcin Zaniew, Giorgio Piaggio, Miguel Verbitsky, Brynn Levy, Virginia E. Papaioannou, Zoran Gucev, Marijan Saraga, Piotr Adamczyk, David E. Barton, Velibor Tasic, Craig S. Wong, Maria Szczepańska, Rik Westland, Valeria Manca, Jun Zhang, Alba Carrea, Fangming Lin, Robert Pawluch, Pasquale Casale, Landino Allegri, Krzysztof Kiryluk, Matthew G. Sampson, Daniele Cusi, Charlly Kao, Max Werth, Shumyle Alam, Young Ji Na, Claudia Izzi, Isabella Pisani, Mark G Dobson, Grażyna Krzemień, Giovanni Conti, Dorota Drozdz, John M Darlow, Shirlee Shril, Patricia L. Weng, Tze Y Lim, Friedhelm Hildebrandt, Monika Miklaszewska, Giuseppe Masnata, Domenico Santoro, Ana Cristina Simões-e-Silva, Byum Hee Kil, Cathy Mendelsohn, Hakon Hakonarson, Przemysław Sikora, Anna Latos-Bielenska, Simone Sanna-Cherchi, Josep M. Campistol, Anna Krakowska, Cécile Jeanpierre, Pasquale Zamboli, Débora Marques de Miranda, Hope White, Francesco Scolari, Dina Ahram, Ekaterina Batourina, Anna Materna-Kiryluk, Valentina P Capone, Eduardo A. Oliveira, Maddalena Marasa, Tomasz Jarmoliński, Jonathan Barasch, Asaf Vivante, Prem Puri, Ali G. Gharavi, Feng Zhang, Priya Krithivasan, Małgorzata Mizerska-Wasiak, Erin L. Heinzen, Maria K Borszewska-Kornacka, Lida Rodas, Bradley A. Warady, Maddalena Gigante, Agnieszka Szmigielska, Qingxue Liu, Susan L. Furth, Vladimir J Lozanovski, Gian Marco Ghiggeri, Daria Tomczyk, Amsterdam Reproduction & Development (AR&D), ACS - Microcirculation, and Paediatric Nephrology

Subjects
Male, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences, endocrine system diseases, Kidney, 0302 clinical medicine, Copy-number variation, deletion, Urinary Tract, Obstructive uropathy, Genetics, 0303 health sciences, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti, Genomics, digeorge-syndrome, Microdeletion syndrome, 3. Good health, medicine.anatomical_structure, Female, vitamin-a, branching morphogenesis, Chromosome Deletion, candidate genes, renal replacement therapy, congenital, hereditary, and neonatal diseases and abnormalities, DNA Copy Number Variations, Urinary system, Locus (genetics), Biology, Vesicoureteral reflux, Article, 03 medical and health sciences, mental disorders, medicine, Humans, Genetic Predisposition to Disease, genomic disorders, 030304 developmental biology, Vesico-Ureteral Reflux, disease, Extramural, rare variants, medicine.disease, mutations, Urogenital Abnormalities, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2, 824 cases and 21, 498 controls. Affected individuals carried a significant burden of rare exonic (i.e. affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD- CNVs and novel deletions ; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs ; vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12, and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1- p16.3, and 22q11.2 were specific for KA ; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

Published
2019

11. Author Correction: The copy number variation landscape of congenital anomalies of the kidney and urinary tract

Author

Qingxue Liu, Marcin Tkaczyk, Susan L. Furth, Friedhelm Hildebrandt, Adele Mitrotti, Gian Marco Ghiggeri, Max Werth, Landino Allegri, Daniele Cusi, David Fasel, Nan Wu, Brynn Levy, Francesco Scolari, Joanna A.E. van Wijk, Marijan Saraga, Daria Tomczyk, Pasquale Casale, Piotr Adamczyk, Loreto Gesualdo, Giovanni Conti, Przemysław Sikora, Anna Materna-Kiryluk, Prem Puri, Erin L. Heinzen, Claudia Izzi, Domenico Santoro, Anna Krakowska, Isabella Pisani, Miguel Verbitsky, Mark G Dobson, Priya Krithivasan, Cathy Mendelsohn, Maria K Borszewska-Kornacka, Tomasz Jarmoliński, Jeremiah Martino, Dina Ahram, Maddalena Gigante, Zoran Gucev, Patricia L. Weng, Débora Marques de Miranda, Katarzyna Zachwieja, Tze Y Lim, Dorota Drozdz, Shirlee Shril, Maddalena Marasa, Valentina P Capone, Grażyna Krzemień, Marcin Zaniew, Velibor Tasic, Krzysztof Kiryluk, Alba Carrea, Craig S. Wong, Byum Hee Kil, Lida Rodas, Shumyle Alam, Giuseppe Masnata, Monica Bodria, Rik Westland, Bradley A. Warady, Alejandra Perez, David E. Barton, Hakon Hakonarson, Monika Miklaszewska, Vladimir J Lozanovski, Young Ji Na, John M Darlow, Simone Sanna-Cherchi, Ana Cristina Simões-e-Silva, Pasquale Zamboli, Hope White, Jun Zhang, Fangming Lin, Anna Latos-Bielenska, Eduardo A. Oliveira, Charlly Kao, Maria Szczepańska, Jonathan Barasch, Asaf Vivante, Valeria Manca, Ali G. Gharavi, Feng Zhang, Robert Pawluch, Agnieszka Szmigielska, Matthew G. Sampson, Giorgio Piaggio, Josep M. Campistol, Cécile Jeanpierre, Virginia E. Papaioannou, Ekaterina Batourina, and Małgorzata Mizerska-Wasiak

Subjects
0303 health sciences, medicine.medical_specialty, Kidney, Urology department, Published Erratum, General surgery, Urinary system, MEDLINE, Biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Genetics, medicine, Copy-number variation, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

In the version of this article initially published, affiliation 38 incorrectly read “ICNU-Nephrology and Urology Department, Barcelona, Spain”; “Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain” is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article.

Published
2019

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