Author: "Lifton, Richard P." / Topic: genetics - Searchworks@Jio Institute Digital Library Search Results

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1. Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Author: Matuozzo, Daniela, Talouarn, Estelle, Marchal, Astrid, Zhang, Peng, Manry, Jeremy, Seeleuthner, Yoann, Zhang, Yu, Bolze, Alexandre, Chaldebas, Matthieu, Milisavljevic, Baptiste, Gervais, Adrian, Bastard, Paul, Asano, Takaki, Bizien, Lucy, Barzaghi, Federica, Abolhassani, Hassan, Abou Tayoun, Ahmad, Aiuti, Alessandro, Alavi Darazam, Ilad, Allende, Luis M, Alonso-Arias, Rebeca, Arias, Andrés Augusto, Aytekin, Gokhan, Bergman, Peter, Bondesan, Simone, Bryceson, Yenan T, Bustos, Ingrid G, Cabrera-Marante, Oscar, Carcel, Sheila, Carrera, Paola, Casari, Giorgio, Chaïbi, Khalil, Colobran, Roger, Condino-Neto, Antonio, Covill, Laura E, Delmonte, Ottavia M, El Zein, Loubna, Flores, Carlos, Gregersen, Peter K, Gut, Marta, Haerynck, Filomeen, Halwani, Rabih, Hancerli, Selda, Hammarström, Lennart, Hatipoğlu, Nevin, Karbuz, Adem, Keles, Sevgi, Kyheng, Christèle, Leon-Lopez, Rafael, Franco, Jose Luis, Mansouri, Davood, Martinez-Picado, Javier, Metin Akcan, Ozge, Migeotte, Isabelle, Morange, Pierre-Emmanuel, Morelle, Guillaume, Martin-Nalda, Andrea, Novelli, Giuseppe, Novelli, Antonio, Ozcelik, Tayfun, Palabiyik, Figen, Pan-Hammarström, Qiang, de Diego, Rebeca Pérez, Planas-Serra, Laura, Pleguezuelo, Daniel E, Prando, Carolina, Pujol, Aurora, Reyes, Luis Felipe, Rivière, Jacques G, Rodriguez-Gallego, Carlos, Rojas, Julian, Rovere-Querini, Patrizia, Schlüter, Agatha, Shahrooei, Mohammad, Sobh, Ali, Soler-Palacin, Pere, Tandjaoui-Lambiotte, Yacine, Tipu, Imran, Tresoldi, Cristina, Troya, Jesus, van de Beek, Diederik, Zatz, Mayana, Zawadzki, Pawel, Al-Muhsen, Saleh Zaid, Alosaimi, Mohammed Faraj, Alsohime, Fahad M, Baris-Feldman, Hagit, Butte, Manish J, Constantinescu, Stefan N, Cooper, Megan A, Dalgard, Clifton L, Fellay, Jacques, Heath, James R, Lau, Yu-Lung, Lifton, Richard P, Maniatis, Tom, Mogensen, Trine H, von Bernuth, Horst, Lermine, Alban, and Vidaud, Michel
Subjects: Clinical Research, Infectious Diseases, Pneumonia & Influenza, Genetics, Human Genome, Prevention, 2.1 Biological and endogenous factors, Aetiology, Humans, Young Adult, Adult, Middle Aged, COVID-19, SARS-CoV-2, Toll-Like Receptor 3, Toll-Like Receptor 7, Interferon Type I, Autoantibodies, COVID Human Genetic Effort, COVIDeF Study Group, French COVID Cohort Study Group, CoV-Contact Cohort, COVID-STORM Clinicians, COVID Clinicians, Orchestra Working Group, Amsterdam UMC Covid-19 Biobank, NIAID-USUHS COVID Study Group, Immunity, Rare variants, Type I interferon, Clinical Sciences
Abstract: BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P = 1.1 × 10-4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3-8.2], P = 2.1 × 10-4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1-2635.4], P = 3.4 × 10-3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3-8.4], P = 7.7 × 10-8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10-5).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
Published: 2023

2. Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia

Author: Dong, Weilai, Wong, Karen HY, Liu, Youbin, Levy-Sakin, Michal, Hung, Wei-Chien, Li, Mo, Li, Boyang, Jin, Sheng Chih, Choi, Jungmin, Lopez-Giraldez, Francesc, Vaka, Dedeepya, Poon, Annie, Chu, Catherine, Lao, Richard, Balamir, Melek, Movsesyan, Irina, Malloy, Mary J, Zhao, Hongyu, Kwok, Pui-Yan, Kane, John P, Lifton, Richard P, and Pullinger, Clive R
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Heart Disease, Biotechnology, Human Genome, Atherosclerosis, Cardiovascular, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Cholesterol, HDL, Genome-Wide Association Study, Heterozygote, Humans, Hypoalphalipoproteinemias, Exome Sequencing, dyslipidemia, genetics, HDL, LDL, lipoproteins, prebeta-1 HDL, reverse cholesterol transport, triglycerides, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract: Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4-36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those with the highest prevalence of damaging variants were ABCA1 (n = 20), STAB1 (n = 9), OSBPL1A (n = 8), CPS1 (n = 8), CD36 (n = 7), LRP1 (n = 6), ABCA8 (n = 6), GOT2 (n = 5), AMPD3 (n = 5), WWOX (n = 4), and IRS1 (n = 4). Binomial analysis for damaging missense or loss-of-function variants identified the ABCA1 and LDLR genes at genome-wide significance. In conclusion, whole-exome sequencing of individuals with low HDL-C showed the burden of damaging rare variants in the ABCA1 and LDLR genes is particularly high and revealed numerous occurrences in HDL candidate genes, including many genes identified in genome-wide association study reports. Many of these genes are involved in cancer biology, which accords with epidemiologic findings of the association of HDL deficiency with increased risk of cancer, thus presenting a new area of interest in HDL genomics.
Published: 2022

3. EM-mosaic detects mosaic point mutations that contribute to congenital heart disease

Author: Hsieh, Alexander, Morton, Sarah U, Willcox, Jon AL, Gorham, Joshua M, Tai, Angela C, Qi, Hongjian, DePalma, Steven, McKean, David, Griffin, Emily, Manheimer, Kathryn B, Bernstein, Daniel, Kim, Richard W, Newburger, Jane W, Porter, George A, Srivastava, Deepak, Tristani-Firouzi, Martin, Brueckner, Martina, Lifton, Richard P, Goldmuntz, Elizabeth, Gelb, Bruce D, Chung, Wendy K, Seidman, Christine E, Seidman, JG, and Shen, Yufeng
Subjects: Biological Sciences, Genetics, Cardiovascular, Human Genome, Clinical Research, Heart Disease, 2.1 Biological and endogenous factors, Aetiology, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Adolescent, Adult, Child, Child, Preschool, Heart Defects, Congenital, Humans, Infant, Mosaicism, Point Mutation, Software, Young Adult, Mosaic, Somatic, Congenital heart disease, Exome sequencing, Clinical Sciences
Abstract: BackgroundThe contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.MethodsWe developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available.ResultsEM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.ConclusionsWe estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses.
Published: 2020

4. De novo Damaging Variants, Clinical Phenotypes and Post-Operative Outcomes in Congenital Heart Disease

Author: Boskovski, Marko T, Homsy, Jason, Nathan, Meena, Sleeper, Lynn A, Morton, Sarah, Manheimer, Kathryn B, Tai, Angela, Gorham, Joshua, Lewis, Matthew, Swartz, Michael, Alfieris, George M, Bacha, Emile A, Karimi, Mohsen, Meyer, David, Nguyen, Khanh, Bernstein, Daniel, Romano-Adesman, Angela, Porter, George A, Goldmuntz, Elizabeth, Chung, Wendy K, Srivastava, Deepak, Kaltman, Jonathan R, Tristani-Firouzi, Martin, Lifton, Richard, Roberts, Amy E, Gaynor, J William, Gelb, Bruce D, Kim, Richard, Seidman, Jonathan G, Brueckner, Martina, Mayer, John E, Newburger, Jane W, and Seidman, Christine E
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Genetics, Patient Safety, Congenital Structural Anomalies, Clinical Research, Human Genome, Transplantation, Heart Disease, Cardiovascular, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Adolescent, Child, Child, Preschool, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 3, DNA Copy Number Variations, Female, Heart Defects, Congenital, Heart Transplantation, Humans, Infant, Kaplan-Meier Estimate, Machine Learning, Male, Odds Ratio, Phenotype, Proportional Hazards Models, Exome Sequencing, genomics, congenital heart disease, heart transplantation, mortality, survival, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract: BackgroundDe novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.MethodsWe studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network).ResultsTwo hundred ninety-four patients (11.7%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (P=5.63×10-12). In 1268 patients (50.4%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; P=5.33×10-04) and longer times to final extubation (hazard ratio, 0.74; P=0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (P=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; P=0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; P=1.61×10-05) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation.ConclusionsIn patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.
Published: 2020

5. Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects

Author: Edwards, Jonathan J, Rouillard, Andrew D, Fernandez, Nicolas F, Wang, Zichen, Lachmann, Alexander, Shankaran, Sunita S, Bisgrove, Brent W, Demarest, Bradley, Turan, Nahid, Srivastava, Deepak, Bernstein, Daniel, Deanfield, John, Giardini, Alessandro, Porter, George, Kim, Richard, Roberts, Amy E, Newburger, Jane W, Goldmuntz, Elizabeth, Brueckner, Martina, Lifton, Richard P, Seidman, Christine E, Chung, Wendy K, Tristani-Firouzi, Martin, Yost, H Joseph, Ma’ayan, Avi, and Gelb, Bruce D
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Cardiovascular, Heart Disease, Genetics, Aetiology, 2.1 Biological and endogenous factors, congenital heart disease, systems biology, translational genomics, CHD, congenital heart disease, CORUM, Comprehensive Resource of Mammalian Protein Complexes, CRISPR, clustered regularly interspaced short palindromic repeats, CTD, conotruncal defect, GOBP, Gene Ontology biological processes, HHE, high heart expression, HLHS, hypoplastic left heart syndrome, HTX, heterotaxy, LVOTO, left ventricular outflow tract obstruction, MGI, Mouse Genome Informatics, PCGC, Pediatric Cardiac Genomics Consortium, PPI, protein-protein interaction, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular medicine and haematology
Abstract: Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development.
Published: 2020

6. CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris

Author: Craiglow, Brittany G, Boyden, Lynn M, Hu, Ronghua, Virtanen, Marie, Su, John, Rodriguez, Gabriela, McCarthy, Catherine, Luna, Paula, Larralde, Margarita, Humphrey, Stephen, Holland, Kristen E, Hogeling, Marcia, Hidalgo-Matlock, Benjamin, Ferrari, Bruno, Fernandez-Faith, Esteban, Drolet, Beth, Cordoro, Kelly M, Bowcock, Anne M, Antaya, Richard J, Ashack, Kurt, Ashack, Richard J, Lifton, Richard P, Milstone, Leonard M, Paller, Amy S, and Choate, Keith A
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Psoriasis, Rare Diseases, Genetics, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Age of Onset, CARD Signaling Adaptor Proteins, Child, Child, Preschool, Dermatologic Agents, Facial Dermatoses, Genetic Testing, Guanylate Cyclase, Humans, Infant, Infant, Newborn, Membrane Proteins, Phenotype, Pityriasis Rubra Pilaris, Retreatment, Skin Diseases, Papulosquamous, Ustekinumab, CARD14, genetics, pityriasis rubra pilaris, psoriasis, treatment, ustekinumab, Dermatology & Venereal Diseases, Clinical sciences
Abstract: BackgroundHeterozygous mutations in caspase recruitment domain family member 14 gene (CARD14) have been shown to be associated with psoriasis and familial pityriasis rubra pilaris (PRP). Many subjects with CARD14 mutations display features of both disorders, which can result in diagnostic uncertainty. In addition, these eruptions are often recalcitrant to conventional psoriasis therapies such as methotrexate, oral retinoids, and tumor necrosis factor-α inhibitors.ObjectiveWe sought to describe the clinical characteristics, family history, and response to therapy in subjects with papulosquamous eruptions due to mutations in CARD14.MethodsSubjects were referred for genetic testing as part of a registry of subjects with inherited disorders of keratinization. DNA was isolated from blood or saliva, and multiplex targeted sequencing or whole exome sequencing was performed. Clinical histories of subjects with CARD14 mutations were reviewed.ResultsWe identified 15 kindreds with CARD14-associated papulosquamous eruption (CAPE). Characteristic features of CAPE include early age of onset; prominent involvement of the cheeks, chin, and ears; family history of psoriasis or PRP; minimal response to conventional topical and systemic psoriasis therapies; and improvement with ustekinumab.LimitationsRelatively small sample size.ConclusionsMany subjects with CARD14 mutations display characteristics of both psoriasis and PRP. We propose the term CARD14-associated papulosquamous eruption to describe this spectrum of disease. Subjects with clinical features suggestive of CAPE should undergo CARD14 sequencing and may benefit from treatment with ustekinumab.
Published: 2018

7. The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders

Author: Willsey, A Jeremy, Morris, Montana T, Wang, Sheng, Willsey, Helen R, Sun, Nawei, Teerikorpi, Nia, Baum, Tierney B, Cagney, Gerard, Bender, Kevin J, Desai, Tejal A, Srivastava, Deepak, Davis, Graeme W, Doudna, Jennifer, Chang, Edward, Sohal, Vikaas, Lowenstein, Daniel H, Li, Hao, Agard, David, Keiser, Michael J, Shoichet, Brian, von Zastrow, Mark, Mucke, Lennart, Finkbeiner, Steven, Gan, Li, Sestan, Nenad, Ward, Michael E, Huttenhain, Ruth, Nowakowski, Tomasz J, Bellen, Hugo J, Frank, Loren M, Khokha, Mustafa K, Lifton, Richard P, Kampmann, Martin, Ideker, Trey, State, Matthew W, and Krogan, Nevan J
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Mental Health, Schizophrenia, Autism, Intellectual and Developmental Disabilities (IDD), Neurosciences, Brain Disorders, Human Genome, Aetiology, Underpinning research, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Good Health and Well Being, Chromosome Mapping, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Neurobiology, Neurodevelopmental Disorders, Neuropsychiatry, Systems Biology, convergence, genetics, interactome, network, neurodevelopmental disorder, pathway, proteomics, psychiatric cell map initiative, psychiatric disorder, psychiatry, systems biology, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract: Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.
Published: 2018

8. Molecular and cellular reorganization of neural circuits in the human lineage

Author: Sousa, André MM, Zhu, Ying, Raghanti, Mary Ann, Kitchen, Robert R, Onorati, Marco, Tebbenkamp, Andrew TN, Stutz, Bernardo, Meyer, Kyle A, Li, Mingfeng, Kawasawa, Yuka Imamura, Liu, Fuchen, Perez, Raquel Garcia, Mele, Marta, Carvalho, Tiago, Skarica, Mario, Gulden, Forrest O, Pletikos, Mihovil, Shibata, Akemi, Stephenson, Alexa R, Edler, Melissa K, Ely, John J, Elsworth, John D, Horvath, Tamas L, Hof, Patrick R, Hyde, Thomas M, Kleinman, Joel E, Weinberger, Daniel R, Reimers, Mark, Lifton, Richard P, Mane, Shrikant M, Noonan, James P, State, Matthew W, Lein, Ed S, Knowles, James A, Marques-Bonet, Tomas, Sherwood, Chet C, Gerstein, Mark B, and Sestan, Nenad
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Neurosciences, Brain Disorders, 1.1 Normal biological development and functioning, Underpinning research, Neurological, Animals, Gene Expression Profiling, Humans, Interneurons, Macaca, Neocortex, Neural Pathways, Pan troglodytes, Phylogeny, Species Specificity, Transcriptome, General Science & Technology
Abstract: To better understand the molecular and cellular differences in brain organization between human and nonhuman primates, we performed transcriptome sequencing of 16 regions of adult human, chimpanzee, and macaque brains. Integration with human single-cell transcriptomic data revealed global, regional, and cell-type-specific species expression differences in genes representing distinct functional categories. We validated and further characterized the human specificity of genes enriched in distinct cell types through histological and functional analyses, including rare subpallial-derived interneurons expressing dopamine biosynthesis genes enriched in the human striatum and absent in the nonhuman African ape neocortex. Our integrated analysis of the generated data revealed diverse molecular and cellular features of the phylogenetic reorganization of the human brain across multiple levels, with relevance for brain function and disease.
Published: 2017

9. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

Author: Jin, Sheng Chih, Homsy, Jason, Zaidi, Samir, Lu, Qiongshi, Morton, Sarah, DePalma, Steven R, Zeng, Xue, Qi, Hongjian, Chang, Weni, Sierant, Michael C, Hung, Wei-Chien, Haider, Shozeb, Zhang, Junhui, Knight, James, Bjornson, Robert D, Castaldi, Christopher, Tikhonoa, Irina R, Bilguvar, Kaya, Mane, Shrikant M, Sanders, Stephan J, Mital, Seema, Russell, Mark W, Gaynor, J William, Deanfield, John, Giardini, Alessandro, Porter, George A, Srivastava, Deepak, Lo, Cecelia W, Shen, Yufeng, Watkins, W Scott, Yandell, Mark, Yost, H Joseph, Tristani-Firouzi, Martin, Newburger, Jane W, Roberts, Amy E, Kim, Richard, Zhao, Hongyu, Kaltman, Jonathan R, Goldmuntz, Elizabeth, Chung, Wendy K, Seidman, Jonathan G, Gelb, Bruce D, Seidman, Christine E, Lifton, Richard P, and Brueckner, Martina
Subjects: Biological Sciences, Genetics, Cardiovascular, Pediatric, Congenital Structural Anomalies, Brain Disorders, Heart Disease, Heart Disease - Coronary Heart Disease, 2.1 Biological and endogenous factors, Aetiology, Adult, Autistic Disorder, Cardiac Myosins, Case-Control Studies, Child, Exome, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Growth Differentiation Factor 1, Heart Defects, Congenital, Heterozygote, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Mutation, Myosin Heavy Chains, Pedigree, Risk, Vascular Endothelial Growth Factor Receptor-3, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.
Published: 2017

10. Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

Author: Bi, Mark, Zhao, Siming, Said, Jonathan W, Merino, Maria J, Adeniran, Adebowale J, Xie, Zuoquan, Nawaf, Cayce B, Choi, Jaehyuk, Belldegrun, Arie S, Pantuck, Allan J, Kluger, Harriet M, Bilgüvar, Kaya, Lifton, Richard P, and Shuch, Brian
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Rare Diseases, Biotechnology, Cancer, Kidney Disease, Aetiology, 2.1 Biological and endogenous factors, Aged, Carcinoma, Renal Cell, Cell Dedifferentiation, DNA Mismatch Repair, DNA-Binding Proteins, Exome, Female, Genes, p53, Humans, Kidney Neoplasms, Loss of Heterozygosity, Male, Middle Aged, Mutation, Nuclear Proteins, Oncogenes, Polymorphism, Single Nucleotide, Prognosis, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin Thiolesterase, kidney cancer, sarcomatoid, transformation, p53, dedifferentiation
Abstract: The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10(-4)), increased frequency of nonsynonymous SSNVs in Pan-Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10(-17)); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers AT-rich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.
Published: 2016

11. Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome

Author: Boyden, Lynn M, Kam, Chen Y, Hernández-Martín, Angela, Zhou, Jing, Craiglow, Brittany G, Sidbury, Robert, Mathes, Erin F, Maguiness, Sheilagh M, Crumrine, Debra A, Williams, Mary L, Hu, Ronghua, Lifton, Richard P, Elias, Peter M, Green, Kathleen J, and Choate, Keith A
Subjects: Genetics, Pediatric, Biotechnology, Heart Disease, Congenital Structural Anomalies, Rare Diseases, Clinical Research, Cardiovascular, Aetiology, 2.1 Biological and endogenous factors, Skin, Amino Acid Sequence, Cardiomyopathies, Child, Child, Preschool, Connexin 43, Desmoplakins, Desmosomes, Female, Humans, Infant, Male, Molecular Sequence Data, Mutation, Missense, Myocardium, Protein Transport, Sequence Alignment, Skin Diseases, Genetic, Syndrome, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin.
Published: 2016

12. Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma

Author: Hedberg, Matthew L, Goh, Gerald, Chiosea, Simion I, Bauman, Julie E, Freilino, Maria L, Zeng, Yan, Wang, Lin, Diergaarde, Brenda B, Gooding, William E, Lui, Vivian WY, Herbst, Roy S, Lifton, Richard P, and Grandis, Jennifer R
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Genetics, Cancer, Rare Diseases, Dental/Oral and Craniofacial Disease, Human Genome, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Adult, Aged, Carcinoma, Squamous Cell, Dasatinib, Discoidin Domain Receptors, Female, Head and Neck Neoplasms, Humans, Inositol 1, 4, 5-Trisphosphate Receptors, Lymphatic Metastasis, Male, Middle Aged, Mutation, Neoplasm Recurrence, Local, Receptor Protein-Tyrosine Kinases, Receptors, Mitogen, Squamous Cell Carcinoma of Head and Neck, Medical and Health Sciences, Immunology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract: BackgroundRecurrence and/or metastasis occurs in more than half of patients with head and neck squamous cell carcinoma (HNSCC), and these events pose the greatest threats to long-term survival. We set out to identify genetic alterations that underlie recurrent/metastatic HNSCC.MethodsWhole-exome sequencing (WES) was performed on genomic DNA extracted from fresh-frozen whole blood and patient-matched tumor pairs from 13 HNSCC patients with synchronous lymph node metastases and 10 patients with metachronous recurrent tumors. Mutational concordance within and between tumor pairs was used to analyze the spatiotemporal evolution of HNSCC in individual patients and to identify potential therapeutic targets for functional evaluation.ResultsApproximately 86% and 60% of single somatic nucleotide variants (SSNVs) identified in synchronous nodal metastases and metachronous recurrent tumors, respectively, were transmitted from the primary index tumor. Genes that were mutated in more than one metastatic or recurrent tumor, but not in the respective primary tumors, include C17orf104, inositol 1,4,5-trisphosphate receptor, type 3 (ITPR3), and discoidin domain receptor tyrosine kinase 2 (DDR2). Select DDR2 mutations have been shown to confer enhanced sensitivity to SRC-family kinase (SFK) inhibitors in other malignancies. Similarly, HNSCC cell lines harboring endogenous and engineered DDR2 mutations were more sensitive to the SFK inhibitor dasatinib than those with WT DDR2.ConclusionIn this WES study of patient-matched tumor pairs in HNSCC, we found synchronous lymph node metastases to be genetically more similar to their paired index primary tumors than metachronous recurrent tumors. This study outlines a compendium of somatic mutations in primary, metastatic, and/or recurrent HNSCC cancers, with potential implications for precision medicine approaches.FundingNational Cancer Institute, American Cancer Society, Agency for Science, Technology and Research of Singapore, and Gilead Sciences Inc.
Published: 2016

13. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

Author: Homsy, Jason, Zaidi, Samir, Shen, Yufeng, Ware, James S, Samocha, Kaitlin E, Karczewski, Konrad J, DePalma, Steven R, McKean, David, Wakimoto, Hiroko, Gorham, Josh, Jin, Sheng Chih, Deanfield, John, Giardini, Alessandro, Porter, George A, Kim, Richard, Bilguvar, Kaya, López-Giráldez, Francesc, Tikhonova, Irina, Mane, Shrikant, Romano-Adesman, Angela, Qi, Hongjian, Vardarajan, Badri, Ma, Lijiang, Daly, Mark, Roberts, Amy E, Russell, Mark W, Mital, Seema, Newburger, Jane W, Gaynor, J William, Breitbart, Roger E, Iossifov, Ivan, Ronemus, Michael, Sanders, Stephan J, Kaltman, Jonathan R, Seidman, Jonathan G, Brueckner, Martina, Gelb, Bruce D, Goldmuntz, Elizabeth, Lifton, Richard P, Seidman, Christine E, and Chung, Wendy K
Subjects: Congenital Structural Anomalies, Genetics, Pediatric, Heart Disease, Cardiovascular, Brain, Child, Congenital Abnormalities, Exome, Heart Defects, Congenital, Humans, Mutation, Nervous System Malformations, Neurogenesis, Prognosis, RNA Splicing, RNA Splicing Factors, RNA, Messenger, RNA-Binding Proteins, Repressor Proteins, Transcription, Genetic, General Science & Technology
Abstract: Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.
Published: 2015

14. Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti

Author: Choate, Keith A, Lu, Yin, Zhou, Jing, Elias, Peter M, Zaidi, Samir, Paller, Amy S, Farhi, Anita, Nelson-Williams, Carol, Crumrine, Debra, Milstone, Leonard M, and Lifton, Richard P
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Pediatric, Skin, Adult, Age of Onset, Amino Acid Sequence, Cell Line, Tumor, Cell Nucleus, Child, Child, Preschool, Chromosomes, Human, Pair 12, Cytoskeleton, Frameshift Mutation, Humans, Ichthyosis, Intermediate Filaments, Keratin-1, Keratinocytes, Loss of Heterozygosity, Male, Molecular Sequence Data, Mosaicism, Phenotype, Polymorphism, Single Nucleotide, Protein Transport, Transfection, Medical and Health Sciences, Immunology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract: Widespread reversion of genetic disease is rare; however, such events are particularly evident in some skin disorders in which normal clones develop on a background of affected skin. We previously demonstrated that mutations in keratin 10 (KRT10) cause ichthyosis with confetti (IWC), a severe dominant disorder that is characterized by progressive development of hundreds of normal skin spots via revertant mosaicism. Here, we report on a clinical and histological IWC subtype in which affected subjects have red, scaly skin at birth, experience worsening palmoplantar keratoderma in childhood, and develop hundreds of normal skin spots, beginning at around 20 years of age, that increase in size and number over time. We identified a causal de novo mutation in keratin 1 (KRT1). Similar to IWC-causing KRT10 mutations, this mutation in KRT1 resulted in a C-terminal frameshift, replacing 22 C-terminal amino acids with an alternate 30-residue peptide. Mutant KRT1 caused partial collapse of the cytoplasmic intermediate filament network and mislocalized to the nucleus. As with KRT10 mutations causing IWC, reversion of KRT1 mutations occurred via mitotic recombination. Because reversion is not observed with other disease-causing keratin mutations, the results of this study implicate KRT1 and KRT10 C-terminal frameshift mutations in the high frequency of revertant mosaicism in IWC.
Published: 2015

15. Increased Frequency of De Novo Copy Number Variants in Congenital Heart Disease by Integrative Analysis of Single Nucleotide Polymorphism Array and Exome Sequence Data

Author: Glessner, Joseph T, Bick, Alexander G, Ito, Kaoru, Homsy, Jason, Rodriguez-Murillo, Laura, Fromer, Menachem, Mazaika, Erica, Vardarajan, Badri, Italia, Michael, Leipzig, Jeremy, DePalma, Steven R, Golhar, Ryan, Sanders, Stephan J, Yamrom, Boris, Ronemus, Michael, Iossifov, Ivan, Willsey, A Jeremy, State, Matthew W, Kaltman, Jonathan R, White, Peter S, Shen, Yufeng, Warburton, Dorothy, Brueckner, Martina, Seidman, Christine, Goldmuntz, Elizabeth, Gelb, Bruce D, Lifton, Richard, Seidman, Jonathan, Hakonarson, Hakon, and Chung, Wendy K
Subjects: Human Genome, Pediatric, Congenital Structural Anomalies, Genetics, Cardiovascular, Heart Disease, Aetiology, 2.1 Biological and endogenous factors, Case-Control Studies, Cohort Studies, DNA Copy Number Variations, Exome, Gene Frequency, Gene Regulatory Networks, Heart Defects, Congenital, Humans, Molecular Sequence Data, Polymorphism, Single Nucleotide, DNA copy number variations, genomics, microarray analysis, polymorphism, single nucleotide, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract: RationaleCongenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis.ObjectiveTo determine the contribution of de novo copy number variants (CNVs) in the pathogenesis of sporadic CHD.Methods and resultsWe studied 538 CHD trios using genome-wide dense single nucleotide polymorphism arrays and whole exome sequencing. Results were experimentally validated using digital droplet polymerase chain reaction. We compared validated CNVs in CHD cases with CNVs in 1301 healthy control trios. The 2 complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either single nucleotide polymorphism array (P=7×10(-5); odds ratio, 4.6) or whole exome sequencing data (P=6×10(-4); odds ratio, 3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic (P=0.02; odds ratio, 2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in whole exome sequencing and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions.ConclusionsWe demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.
Published: 2014

16. Rare deleterious mutations of the gene EFR3A in autism spectrum disorders.

Author: Gupta, Abha, Pirruccello, Michelle, Cheng, Feng, Kang, Hyo, Fernandez, Thomas, Baskin, Jeremy, Choi, Murim, Liu, Li, Ercan-Sencicek, Adife, Murdoch, John, Klei, Lambertus, Neale, Benjamin, Franjic, Daniel, Daly, Mark, Lifton, Richard, De Camilli, Pietro, Zhao, Hongyu, Sestan, Nenad, and State, Matthew
Subjects: Autism spectrum disorder, EFR3A, Genetics, Phosphoinositide metabolism, Rare variants, Synapse
Abstract: BACKGROUND: Whole-exome sequencing studies in autism spectrum disorder (ASD) have identified de novo mutations in novel candidate genes, including the synaptic gene Eighty-five Requiring 3A (EFR3A). EFR3A is a critical component of a protein complex required for the synthesis of the phosphoinositide PtdIns4P, which has a variety of functions at the neural synapse. We hypothesized that deleterious mutations in EFR3A would be significantly associated with ASD. METHODS: We conducted a large case/control association study by deep resequencing and analysis of whole-exome data for coding and splice site variants in EFR3A. We determined the potential impact of these variants on protein structure and function by a variety of conservation measures and analysis of the Saccharomyces cerevisiae Efr3 crystal structure. We also analyzed the expression pattern of EFR3A in human brain tissue. RESULTS: Rare nonsynonymous mutations in EFR3A were more common among cases (16 / 2,196 = 0.73%) than matched controls (12 / 3,389 = 0.35%) and were statistically more common at conserved nucleotides based on an experiment-wide significance threshold (P = 0.0077, permutation test). Crystal structure analysis revealed that mutations likely to be deleterious were also statistically more common in cases than controls (P = 0.017, Fisher exact test). Furthermore, EFR3A is expressed in cortical neurons, including pyramidal neurons, during human fetal brain development in a pattern consistent with ASD-related genes, and it is strongly co-expressed (P
Published: 2014

17. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.

Author: Lim, Young H, Ovejero, Diana, Sugarman, Jeffrey S, Deklotz, Cynthia MC, Maruri, Ann, Eichenfield, Lawrence F, Kelley, Patrick K, Jüppner, Harald, Gottschalk, Michael, Tifft, Cynthia J, Gafni, Rachel I, Boyce, Alison M, Cowen, Edward W, Bhattacharyya, Nisan, Guthrie, Lori C, Gahl, William A, Golas, Gretchen, Loring, Erin C, Overton, John D, Mane, Shrikant M, Lifton, Richard P, Levy, Moise L, Collins, Michael T, and Choate, Keith A
Subjects: Skin, Humans, Nevus, Nevus, Pigmented, Skin Neoplasms, Osteomalacia, Hypophosphatemia, GTP Phosphohydrolases, Fibroblast Growth Factors, Membrane Proteins, Sequence Analysis, DNA, Gene Expression Regulation, Developmental, Mutation, Adolescent, Child, Female, Male, Proto-Oncogene Proteins p21(ras), Exome, Fibroblast Growth Factor-23, Kidney Disease, Rare Diseases, Genetics, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.
Published: 2014

18. ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption

Author: Ashraf, Shazia, Gee, Heon Yung, Woerner, Stephanie, Xie, Letian X, Vega-Warner, Virginia, Lovric, Svjetlana, Fang, Humphrey, Song, Xuewen, Cattran, Daniel C, Avila-Casado, Carmen, Paterson, Andrew D, Nitschké, Patrick, Bole-Feysot, Christine, Cochat, Pierre, Esteve-Rudd, Julian, Haberberger, Birgit, Allen, Susan J, Zhou, Weibin, Airik, Rannar, Otto, Edgar A, Barua, Moumita, Al-Hamed, Mohamed H, Kari, Jameela A, Evans, Jonathan, Bierzynska, Agnieszka, Saleem, Moin A, Böckenhauer, Detlef, Kleta, Robert, Desoky, Sherif El, Hacihamdioglu, Duygu O, Gok, Faysal, Washburn, Joseph, Wiggins, Roger C, Choi, Murim, Lifton, Richard P, Levy, Shawn, Han, Zhe, Salviati, Leonardo, Prokisch, Holger, Williams, David S, Pollak, Martin, Clarke, Catherine F, Pei, York, Antignac, Corinne, and Hildebrandt, Friedhelm
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Complementary and Integrative Health, Aetiology, 2.1 Biological and endogenous factors, Renal and urogenital, Adolescent, Adrenal Cortex Hormones, Amino Acid Sequence, Animals, Cells, Cultured, Child, Consanguinity, Conserved Sequence, DNA Mutational Analysis, Disease Models, Animal, Drosophila Proteins, Drug Resistance, Exome, Fibroblasts, Gene Knockdown Techniques, Humans, Mitochondria, Molecular Sequence Data, Mutation, Nephrotic Syndrome, Podocytes, Protein Kinases, Rats, Sequence Alignment, Sequence Homology, Amino Acid, Ubiquinone, Young Adult, Zebrafish, Zebrafish Proteins, Medical and Health Sciences, Immunology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract: Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.
Published: 2013

19. Mutations in DSTYK and Dominant Urinary Tract Malformations

Author: Sanna-Cherchi, Simone, Sampogna, Rosemary V, Papeta, Natalia, Burgess, Katelyn E, Nees, Shannon N, Perry, Brittany J, Choi, Murim, Bodria, Monica, Liu, Yan, Weng, Patricia L, Lozanovski, Vladimir J, Verbitsky, Miguel, Lugani, Francesca, Sterken, Roel, Paragas, Neal, Caridi, Gianluca, Carrea, Alba, Dagnino, Monica, Materna-Kiryluk, Anna, Santamaria, Giuseppe, Murtas, Corrado, Ristoska-Bojkovska, Nadica, Izzi, Claudia, Kacak, Nilgun, Bianco, Beatrice, Giberti, Stefania, Gigante, Maddalena, Piaggio, Giorgio, Gesualdo, Loreto, Vukic, Durdica Kosuljandic, Vukojevic, Katarina, Saraga-Babic, Mirna, Saraga, Marijan, Gucev, Zoran, Allegri, Landino, Latos-Bielenska, Anna, Casu, Domenica, State, Matthew, Scolari, Francesco, Ravazzolo, Roberto, Kiryluk, Krzysztof, Al-Awqati, Qais, D'Agati, Vivette D, Drummond, Iain A, Tasic, Velibor, Lifton, Richard P, Ghiggeri, Gian Marco, and Gharavi, Ali G
Subjects: Urologic Diseases, Pediatric, Congenital Structural Anomalies, Human Genome, Kidney Disease, Biotechnology, Genetics, Clinical Research, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, Renal and urogenital, Adult, Animals, Base Sequence, Child, Exome, Female, Gene Knockdown Techniques, Genetic Linkage, Genome-Wide Association Study, Heterozygote, Humans, Infant, Kidney, Male, Mice, Molecular Sequence Data, Mutation, Pedigree, RNA, Small Interfering, Receptor-Interacting Protein Serine-Threonine Kinases, Urinary Tract, Urogenital Abnormalities, Young Adult, Medical and Health Sciences, General & Internal Medicine
Abstract: BackgroundCongenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.MethodsWe performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies.ResultsLinkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.ConclusionsWe detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).
Published: 2013

20. Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO

Author: Clark, Victoria E, Erson-Omay, E Zeynep, Serin, Akdes, Yin, Jun, Cotney, Justin, Özduman, Koray, Avşar, Timuçin, Li, Jie, Murray, Phillip B, Henegariu, Octavian, Yilmaz, Saliha, Günel, Jennifer Moliterno, Carrión-Grant, Geneive, Yılmaz, Baran, Grady, Conor, Tanrıkulu, Bahattin, Bakırcıoğlu, Mehmet, Kaymakçalan, Hande, Caglayan, Ahmet Okay, Sencar, Leman, Ceyhun, Emre, Atik, A Fatih, Bayri, Yaşar, Bai, Hanwen, Kolb, Luis E, Hebert, Ryan M, Omay, S Bulent, Mishra-Gorur, Ketu, Choi, Murim, Overton, John D, Holland, Eric C, Mane, Shrikant, State, Matthew W, Bilgüvar, Kaya, Baehring, Joachim M, Gutin, Philip H, Piepmeier, Joseph M, Vortmeyer, Alexander, Brennan, Cameron W, Pamir, M Necmettin, Kılıç, Türker, Lifton, Richard P, Noonan, James P, Yasuno, Katsuhito, and Günel, Murat
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Brain Disorders, Rare Diseases, Brain Cancer, Neurosciences, Human Genome, Cancer, Adult, Aged, Aged, 80 and over, Brain Neoplasms, Chromosomes, Human, Pair 22, DNA Mutational Analysis, Female, Genes, Neurofibromatosis 2, Genomic Instability, Genomics, Humans, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors, Male, Meningeal Neoplasms, Meningioma, Middle Aged, Mutation, Neoplasm Grading, Proto-Oncogene Proteins c-akt, Receptors, G-Protein-Coupled, Smoothened Receptor, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, General Science & Technology
Abstract: We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.
Published: 2013

21. Copy-Number Disorders Are a Common Cause of Congenital Kidney Malformations

Author: Sanna-Cherchi, Simone, Kiryluk, Krzysztof, Burgess, Katelyn E, Bodria, Monica, Sampson, Matthew G, Hadley, Dexter, Nees, Shannon N, Verbitsky, Miguel, Perry, Brittany J, Sterken, Roel, Lozanovski, Vladimir J, Materna-Kiryluk, Anna, Barlassina, Cristina, Kini, Akshata, Corbani, Valentina, Carrea, Alba, Somenzi, Danio, Murtas, Corrado, Ristoska-Bojkovska, Nadica, Izzi, Claudia, Bianco, Beatrice, Zaniew, Marcin, Flogelova, Hana, Weng, Patricia L, Kacak, Nilgun, Giberti, Stefania, Gigante, Maddalena, Arapovic, Adela, Drnasin, Kristina, Caridi, Gianluca, Curioni, Simona, Allegri, Franca, Ammenti, Anita, Ferretti, Stefania, Goj, Vinicio, Bernardo, Luca, Jobanputra, Vaidehi, Chung, Wendy K, Lifton, Richard P, Sanders, Stephan, State, Matthew, Clark, Lorraine N, Saraga, Marijan, Padmanabhan, Sandosh, Dominiczak, Anna F, Foroud, Tatiana, Gesualdo, Loreto, Gucev, Zoran, Allegri, Landino, Latos-Bielenska, Anna, Cusi, Daniele, Scolari, Francesco, Tasic, Velibor, Hakonarson, Hakon, Ghiggeri, Gian Marco, and Gharavi, Ali G
Subjects: Prevention, Kidney Disease, Human Genome, Genetics, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Renal and urogenital, Case-Control Studies, Chromosome Aberrations, DNA Copy Number Variations, Genetic Association Studies, Genotype, Humans, Kidney Diseases, Molecular Sequence Annotation, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.
Published: 2012

22. Identification of Somatic Mutations in Parathyroid Tumors Using Whole-Exome Sequencing

Author: Cromer, M Kyle, Starker, Lee F, Choi, Murim, Udelsman, Robert, Nelson-Williams, Carol, Lifton, Richard P, and Carling, Tobias
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Cancer, Human Genome, Cancer Genomics, Genetics, Rare Diseases, 2.1 Biological and endogenous factors, Adenoma, Cohort Studies, DNA Mutational Analysis, DNA, Neoplasm, Enhancer of Zeste Homolog 2 Protein, Exons, Humans, Multiple Endocrine Neoplasia Type 1, Mutation, Parathyroid Neoplasms, Polycomb Repressive Complex 2, Polymerase Chain Reaction, Reproducibility of Results, Sequence Analysis, DNA, Paediatrics and Reproductive Medicine, Endocrinology & Metabolism, Clinical sciences
Abstract: ContextThe underlying molecular alterations causing sporadic parathyroid adenomas that drive primary hyperparathyroidism have not been thoroughly defined.ObjectiveThe aim of the study was to investigate the occurrence of somatic mutations driving tumor formation and progression in sporadic parathyroid adenoma using whole-exome sequencing.DesignEight matched tumor-constitutional DNA pairs from patients with sporadic parathyroid adenomas underwent whole-exome capture and high-throughput sequencing. Selected genes were analyzed for mutations in an additional 185 parathyroid adenomas.ResultsFour of eight tumors displayed a frame shift deletion or nonsense mutation in MEN1, which was accompanied by loss of heterozygosity of the remaining wild-type allele. No other mutated genes were shared among the eight tumors. One tumor harbored a Y641N mutation of the histone methyltransferase EZH2 gene, previously linked to myeloid and lymphoid malignancy formation. Targeted sequencing in the additional 185 parathyroid adenomas revealed a high rate of MEN1 mutations (35%). Furthermore, this targeted sequencing identified an additional parathyroid adenoma that contained the identical, somatic EZH2 mutation that was found by exome sequencing.ConclusionThis study confirms the frequent role of the loss of heterozygosity of chromosome 11 and MEN1 gene alterations in sporadic parathyroid adenomas and implicates a previously unassociated methyltransferase gene, EZH2, in endocrine tumorigenesis.
Published: 2012

23. Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis

Author: Ahram, Dina F, Lim, Tze Y, Ke, Juntao, Jin, Gina, Verbitsky, Miguel, Bodria, Monica, Kil, Byum Hee, Chatterjee, Debanjana, Piva, Stacy E, Marasa, Maddalena, Zhang, Jun Y, Cocchi, Enrico, Caridi, Gianluca, Gucev, Zoran, Lozanovski, Vladimir J, Pisani, Isabella, Izzi, Claudia, Savoldi, Gianfranco, Gnutti, Barbara, Capone, Valentina P, Morello, William, Guarino, Stefano, Esposito, Pasquale, Lambert, Sarah, Radhakrishnan, Jai, Appel, Gerald B, Uy, Natalie S, Rao, Maya K, Canetta, Pietro A, Bomback, Andrew S, Nestor, Jordan G, Hays, Thomas, Cohen, David J, Finale Na, Carolina, van Wijk, Joanna A E, La Scola, Claudio, Baraldi, Olga, Tondolo, Francesco, Di Renzo, Dacia, Jamry-Dziurla, Anna, Pezzutto, Alessandro, Manca, Valeria, Mitrotti, Adele, Santoro, Domenico, Conti, Giovanni, Martino, Marida, Giordano, Mario, Gesualdo, Loreto, Zibar, Lada, Masnata, Giuseppe, Bonomini, Mario, Alberti, Daniele, La Manna, Gaetano, Caliskan, Yasar, Ranghino, Andrea, Marzuillo, Pierluigi, Kiryluk, Krzysztof, Krzemień, Grażyna, Miklaszewska, Monika, Lin, Fangming, Montini, Giovanni, Scolari, Francesco, Fiaccadori, Enrico, Arapović, Adela, Saraga, Marijan, McKiernan, James, Alam, Shumyle, Zaniew, Marcin, Szczepańska, Maria, Szmigielska, Agnieszka, Sikora, Przemysław, Drożdż, Dorota, Mizerska-Wasiak, Malgorzata, Mane, Shrikant, Lifton, Richard P, Tasic, Velibor, Latos-Bielenska, Anna, Gharavi, Ali G, Ghiggeri, Gian Marco, Materna-Kiryluk, Anna, Westland, Rik, Sanna-Cherchi, Simone, Ahram, Dina F, Lim, Tze Y, Ke, Juntao, Jin, Gina, Verbitsky, Miguel, Bodria, Monica, Kil, Byum Hee, Chatterjee, Debanjana, Piva, Stacy E, Marasa, Maddalena, Zhang, Jun Y, Cocchi, Enrico, Caridi, Gianluca, Gucev, Zoran, Lozanovski, Vladimir J, Pisani, Isabella, Izzi, Claudia, Savoldi, Gianfranco, Gnutti, Barbara, Capone, Valentina P, Morello, William, Guarino, Stefano, Esposito, Pasquale, Lambert, Sarah, Radhakrishnan, Jai, Appel, Gerald B, Uy, Natalie S, Rao, Maya K, Canetta, Pietro A, Bomback, Andrew S, Nestor, Jordan G, Hays, Thoma, Cohen, David J, Finale Na, Carolina, van Wijk, Joanna A E, La Scola, Claudio, Baraldi, Olga, Tondolo, Francesco, Di Renzo, Dacia, Jamry-Dziurla, Anna, Pezzutto, Alessandro, Manca, Valeria, Mitrotti, Adele, Santoro, Domenico, Conti, Giovanni, Martino, Marida, Giordano, Mario, Gesualdo, Loreto, Zibar, Lada, Masnata, Giuseppe, Bonomini, Mario, Alberti, Daniele, La Manna, Gaetano, Caliskan, Yasar, Ranghino, Andrea, Marzuillo, Pierluigi, Kiryluk, Krzysztof, Krzemień, Grażyna, Miklaszewska, Monika, Lin, Fangming, Montini, Giovanni, Scolari, Francesco, Fiaccadori, Enrico, Arapović, Adela, Saraga, Marijan, Mckiernan, Jame, Alam, Shumyle, Zaniew, Marcin, Szczepańska, Maria, Szmigielska, Agnieszka, Sikora, Przemysław, Drożdż, Dorota, Mizerska-Wasiak, Malgorzata, Mane, Shrikant, Lifton, Richard P, Tasic, Velibor, Latos-Bielenska, Anna, Gharavi, Ali G, Ghiggeri, Gian Marco, Materna-Kiryluk, Anna, Westland, Rik, and Sanna-Cherchi, Simone
Subjects: Congenital obstructive uropathy, COU, genetics, Nephrology, General Medicine
Abstract: Significance Statement Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. Background Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. Methods We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction (n=321), ureterovesical junction obstruction/congenital megaureter (n=178), and COU not otherwise specified (COU-NOS ; n=234). Results We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. Conclusions We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.
Published: 2023

24. A Mendelian Locus on Chromosome 16 Determines Susceptibility to Doxorubicin Nephropathy in the Mouse

Author: Zheng, Zongyu, Schmidt-Ott, Kai M., Chua, Streamson, Foster, Kirk A., Frankel, Rachelle Z., Pavlidis, Paul, Barasch, Jonathan, Gharavi, Ali G., and Lifton, Richard P.
Published: 2005

25. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations

Author: Bilgüvar, Kaya, Öztürk, Ali Kemal, Louvi, Angeliki, Kwan, Kenneth Y, Choi, Murim, Tatlı, Burak, Yalnızoğlu, Dilek, Tüysüz, Beyhan, Çağlayan, Ahmet Okay, Gökben, Sarenur, Kaymakçalan, Hande, Barak, Tanyeri, Bakırcıoğlu, Mehmet, Yasuno, Katsuhito, Ho, Winson, Sanders, Stephan, Zhu, Ying, Yılmaz, Sanem, Dinçer, Alp, Johnson, Michele H, Bronen, Richard A, Koçer, Naci, Per, Hüseyin, Mane, Shrikant, Pamir, Mehmet Necmettin, Yalçınkaya, Cengiz, Kumandaş, Sefer, Topçu, Meral, Özmen, Meral, Šestan, Nenad, Lifton, Richard P, State, Matthew W, and Günel, Murat
Subjects: Biological Sciences, Genetics, Pediatric, Rare Diseases, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Stem Cell Research, Neurosciences, Congenital Structural Anomalies, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, Animals, Base Sequence, Brain, Brain Diseases, Cell Cycle Proteins, DNA Mutational Analysis, Female, Genes, Recessive, Humans, Male, Mice, Microcephaly, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Pedigree, General Science & Technology
Abstract: The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.
Published: 2010

26. Epigenetic Abnormalities Associated with a Chromosome 18(q21-q22) Inversion and a Gilles de la Tourette Syndrome Phenotype

Author: State, Matthew W., Greally, John M., Cuker, Adam, Bowers, Peter N., Henegariu, Octavian, Morgan, Thomas M., Gunel, Murat, DiLuna, Michael, King, Robert A., Nelson, Carol, Donovan, Abigail, Anderson, George M., Leckman, James F., Hawkins, Trevor, Pauls, David L., Lifton, Richard P., and Ward, David C.
Published: 2003

27. A Translocation Causing Increased α-Klotho Level Results in Hypophosphatemic Rickets and Hyperparathyroidism

Author: Brownstein, Catherine A., Adler, Felix, Nelson-Williams, Carol, Iijima, Junko, Li, Peining, Imura, Akihiro, Nabeshima, Yo-ichi, Reyes-Mugica, Miguel, Carpenter, Thomas O., and Lifton, Richard P.
Published: 2008
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28. Mutation spectrum of congenital heart disease in a consanguineous Turkish population.

Author: Dong, Weilai, Kaymakcalan, Hande, Jin, Sheng Chih, Diab, Nicholas S., Tanıdır, Cansaran, Yalcin, Ali Seyfi Yalim, Ercan‐Sencicek, A. Gulhan, Mane, Shrikant, Gunel, Murat, Lifton, Richard P., Bilguvar, Kaya, and Brueckner, Martina
Subjects: CONSANGUINITY, CONGENITAL heart disease, GENETIC mutation
Abstract: Backgrounds: While many studies agree that consanguinity increases the rate of congenital heart disease (CHD), few genome analyses have been conducted with consanguineous CHD cohorts. Methods: We recruited 73 CHD probands from consanguineous families in Turkey and used whole‐exome sequencing (WES) to identify genetic lesions in these patients. Results: On average, each patient had 6.95 rare damaging homozygous variants, 0.68 of which are loss‐of‐function (LoF) variants. Seven patients (9.6%) carried damaging homozygous variants in five causal CHD genes. Six of those patients exhibited laterality defects (six HTX and one D‐TGA). Three additional patients (4.1%) harbored other types of CHD‐associated genomic alterations, which overall explained 13.7% (10/73) of the cohort. The contribution from recessive variants in our cohort is higher than 1.8% reported from a cohort of 2871 CHD subjects where 5.6% of subjects met the criteria for consanguinity. Conclusions: Our WES screen of a Turkish consanguineous population with structural CHD revealed its unique genetic architecture. Six of seven damaging homozygous variants in CHD causal genes occur in the setting of laterality defects implies a strong contribution from consanguinity to these defects specifically. Our study thus provided valuable information about the genetic landscape of CHD in consanguineous families in Turkey. [ABSTRACT FROM AUTHOR]
Published: 2022
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29. Genetic studies of body mass index yield new insights for obesity biology

Author: Locke, Adam E, Kahali, Bratati, Croteau-Chonka, Damien C, Doney, Alex S F, He, Bing, Heikkilä, Outi, Hietala, Kustaa, Kytö, Janne, Lahermo, Päivi, Lehto, Markku, Österholm, Anne-May, Parkkonen, Maija, Pitkäniemi, Janne, Rosengård-Bärlund, Milla, Eklund, Niina, Saraheimo, Markku, Sarti, Cinzia, Söderlund, Jenny, Soro-Paavonen, Aino, Syreeni, Anna, Thorn, Lena M, Tikkanen, Heikki, Tolonen, Nina, Tryggvason, Karl, Tuomilehto, Jaakko, Estrada, Karol, Wadén, Johan, Gill, Geoffrey V, Prior, Sarah, Guiducci, Candace, Mirel, Daniel B, Taylor, Andrew, Hosseini, Mohsen, Parving, Hans-Henrik, Rossing, Peter, Tarnow, Lise, Eury, Elodie, Ladenvall, Claes, Alhenc-Gelas, François, Lefebvre, Pierre, Rigalleau, Vincent, Roussel, Ronan, Tregouet, David-Alexandre, Maestroni, Anna, Maestroni, Silvia, Falhammar, Henrik, Gu, Tianwei, Folkersen, Lasse, Möllsten, Anna, Cimponeriu, Dan, Mihai, Ioana, Mota, Maria, Mota, Eugen, Serafinceanu, Cristian, Stavarachi, Monica, Hanson, Robert L, Nelson, Robert G, Kretzler, Matthias, Fraser, Ross M, Colhoun, Helen M, Panduru, Nicolae Mircea, Gu, Harvest F, Brismar, Kerstin, Zerbini, Gianpaolo, Hadjadj, Samy, Marre, Michel, Groop, Leif, Lajer, Maria, Bull, Shelley B, Garcia, Melissa E, Waggott, Daryl, Paterson, Andrew D, Savage, David A, Bain, Stephen C, Martin, Finian, Hirschhorn, Joel N, Godson, Catherine, Florez, Jose C, Groop, Per-Henrik, Maxwell, Alexander P, Geller, Frank, Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Peloso, Gina M, Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Buchkovich, Martin L, Mora, Samia, Giedraitis, Vilmantas, Beckmann, Jacques S, Bragg-Gresham, Jennifer L, Chang, Hsing-Y, Demirkan, Ayşe, Den Hertog, Heleen M, Do, Ron, Donnelly, Louise A, Ehret, Georg B, Esko, Tõnu, Feitosa, Mary F, Gigante, Bruna, Ferreira, Teresa, Fischer, Krista, Fontanillas, Pierre, Freitag, Daniel F, Gurdasani, Deepti, Heikkilä, Kauko, Hyppönen, Elina, Isaacs, Aaron, Jackson, Anne U, Esko, Tonu, Go, Alan S, Johansson, Åsa, Johnson, Toby, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E, Li, Xiaohui, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Magnusson, Patrik K E, Mangino, Massimo, Golay, Alain, Mihailov, Evelin, Montasser, May E, Müller-Nurasyid, Martina, Nolte, Ilja M, O'Connell, Jeffrey R, Palmer, Cameron D, Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Goodall, Alison H, Service, Susan K, Shah, Sonia, Shungin, Dmitry, Sidore, Carlo, Song, Ci, Strawbridge, Rona J, Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M, Thorleifsson, Gudmar, Gordon, Scott D, Van den Herik, Evita G, Voight, Benjamin F, Volcik, Kelly A, Waite, Lindsay L, Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Inês, Gorski, Mathias, Been, Latonya F, Bolton, Jennifer L, Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S, Cesana, Giancarlo, Dimitriou, Maria, Doring, Angela, Elliott, Paul, Grabe, Hans-Jörgen, Epstein, Stephen E, Eyjolfsson, Gudmundur Ingi, Goodarzi, Mark O, Grallert, Harald, Gravito, Martha L, Groves, Christopher J, Hallmans, Göran, Hartikainen, Anna-Liisa, Hayward, Caroline, Hernandez, Dena, Hicks, Andrew A, Holm, Hilma, Hung, Yi-Jen, Illig, Thomas, Jones, Michelle R, Kaleebu, Pontiano, Kastelein, John J P, Khaw, Kay-Tee, Kim, Eric, Grammer, Tanja B, Klopp, Norman, Komulainen, Pirjo, Kumari, Meena, Langenberg, Claudia, Lehtimaki, Terho, Lin, Shih-Yi, Lindstrom, Jaana, Loos, Ruth J F, Mach, François, McArdle, Wendy L, Gräßler, Jürgen, Meisinger, Christa, Mitchell, Braxton D, Muller, Gabrielle, Nagaraja, Ramaiah, Narisu, Narisu, Nieminen, Tuomo V M, Nsubuga, Rebecca N, Olafsson, Isleifur, Ong, Ken K, Palotie, Aarno, Grönberg, Henrik, Papamarkou, Theodore, Pomilla, Cristina, Pouta, Anneli, Rader, Daniel J, Reilly, Muredach P, Ridker, Paul M, Rivadeneira, Fernando, Rudan, Igor, Ruokonen, Aimo, Samani, Nilesh, Fall, Tove, Scharnagl, Hubert, Seeley, Janet, Silander, Kaisa, Stančáková, Alena, Stirrups, Kathleen, Swift, Amy J, Tiret, Laurence, Uitterlinden, Andre G, van Pelt, L Joost, Vedantam, Sailaja, Gusto, Gaëlle, Wainwright, Nicholas, Wijmenga, Cisca, Wild, Sarah H, Willemsen, Gonneke, Wilsgaard, Tom, Wilson, James F, Young, Elizabeth H, Zhao, Jing Hua, Adair, Linda S, Arveiler, Dominique, Haessler, Jeffrey, Assimes, Themistocles L, Bandinelli, Stefania, Bennett, Franklyn, Bochud, Murielle, Boehm, Bernhard O, Boomsma, Dorret I, Borecki, Ingrid B, Bornstein, Stefan R, Bovet, Pascal, Burnier, Michel, Hall, Per, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chen, Yii-Der Ida, Collins, Francis S, Cooper, Richard S, Danesh, John, Dedoussis, George, de Faire, Ulf, Feranil, Alan B, Haller, Toomas, Ferrieres, Jean, Ferrucci, Luigi, Freimer, Nelson B, Gieger, Christian, Groop, Leif C, Gudnason, Vilmundur, Gyllensten, Ulf, Hamsten, Anders, Harris, Tamara B, Hingorani, Aroon, Hallmans, Goran, Hofman, Albert, Hovingh, G Kees, Hsiung, Chao Agnes, Humphries, Steve E, Hunt, Steven C, Hveem, Kristian, Iribarren, Carlos, Jarvelin, Marjo-Riitta, Jula, Antti, Hartman, Catharina A, Kähönen, Mika, Kaprio, Jaakko, Kesäniemi, Antero, Kivimaki, Mika, Kooner, Jaspal S, Koudstaal, Peter J, Krauss, Ronald M, Kuh, Diana, Kuusisto, Johanna, Kyvik, Kirsten O, Hassinen, Maija, Laakso, Markku, Lakka, Timo A, Lind, Lars, Lindgren, Cecilia M, Martin, Nicholas G, März, Winfried, McCarthy, Mark I, McKenzie, Colin A, Meneton, Pierre, Metspalu, Andres, Moilanen, Leena, Morris, Andrew D, Munroe, Patricia B, Njølstad, Inger, Pedersen, Nancy L, Power, Chris, Pramstaller, Peter P, Price, Jackie F, Psaty, Bruce M, Quertermous, Thomas, Heard-Costa, Nancy L, Rauramaa, Rainer, Saleheen, Danish, Salomaa, Veikko, Sanghera, Dharambir K, Saramies, Jouko, Schwarz, Peter E H, Sheu, Wayne H-H, Shuldiner, Alan R, Siegbahn, Agneta, Spector, Tim D, Helmer, Quinta, Stefansson, Kari, Strachan, David P, Tayo, Bamidele O, Tremoli, Elena, Uusitupa, Matti, van Duijn, Cornelia M, Vollenweider, Peter, Wallentin, Lars, Wareham, Nicholas J, Hengstenberg, Christian, Whitfield, John B, Wolffenbuttel, Bruce H R, Ordovas, Jose M, Boerwinkle, Eric, Palmer, Colin N A, Thorsteinsdottir, Unnur, Chasman, Daniel I, Rotter, Jerome I, Franks, Paul W, Ripatti, Samuli, Holmen, Oddgeir, Cupples, L Adrienne, Sandhu, Manjinder S, Rich, Stephen S, Boehnke, Michael, Deloukas, Panos, Kathiresan, Sekar, Mohlke, Karen L, Ingelsson, Erik, Abecasis, Gonçalo R, Abecasis, Gonçalo, Hottenga, Jouke-Jan, Caulfield, Mark, Chasman, Dan, Ehret, Georg, Johnson, Andrew, Johnson, Louise, Larson, Martin, Levy, Daniel, James, Alan L, Munroe, Patricia, Newton-Cheh, Christopher, O'Reilly, Paul, Palmas, Walter, Psaty, Bruce, Rice, Kenneth, Smith, Albert, Snider, Harold, Tobin, Martin, Van Duijn, Cornelia, Jeff, Janina M, Verwoert, Germaine, Rice, Kenneth M, Johnson, Andrew D, Smith, Albert V, Tobin, Martin D, Verwoert, Germaine C, Hwang, Shih-Jen, Pihur, Vasyl, O'Reilly, Paul F, Amin, Najaf, Teumer, Alexander, Glazer, Nicole L, Launer, Lenore, Jolley, Jennifer, Aulchenko, Yurii, Heath, Simon, Sõber, Siim, Parsa, Afshin, Arora, Pankaj, Dehghan, Abbas, Zhang, Feng, Lucas, Gavin, Juliusdottir, Thorhildur, Peden, John F, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N, Fava, Cristiano, Kinnunen, Leena, Fox, Ervin R, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Koenig, Wolfgang, Whincup, Peter H, Liu, Yongmei, Shi, Gang, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Nguyen, Khanh-Dung Hoang, Lehtimäki, Terho, Matullo, Giuseppe, Koskenvuo, Markku, Gaunt, Tom R, Onland-Moret, N Charlotte, Cooper, Matthew N, Platou, Carl G P, Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Kratzer, Wolfgang, Braund, Peter S, Kuznetsova, Tatiana, Uiterwaal, Cuno S P M, Adeyemo, Adebowale, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D, Laitinen, Jaana, Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C, Steinle, Nanette I, Grobbee, Diederick E, Arking, Dan E, Kardia, Sharon L, Morrison, Alanna C, Lamina, Claudia, Najjar, Samer, Hadley, David, Brown, Morris J, Connell, John M, Hingorani, Aroon D, Day, Ian N M, Lawlor, Debbie A, Beilby, John P, Lawrence, Robert W, Leander, Karin, Clarke, Robert, Collins, Rory, Hopewell, Jemma C, Ongen, Halit, Dreisbach, Albert W, Li, Yali, Young, J. H., Bis, Joshua C, Viikari, Jorma, Lee, Nanette R, Chen, Ming-Huei, Olden, Matthias, Pattaro, Cristian, Bolton, Judith A Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Lichtner, Peter, Frayling, Timothy M, Islam, Muhammad, Jafar, Tazeen H, Erdmann, Jeanette, Kulkarni, Smita R, Grässler, Jürgen, Howard, Philip, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Weder, Alan B, Lindström, Jaana, Sun, Yan V, Bergman, Richard N, Scott, Laura J, Stringham, Heather M, Peltonen, Leena, Vartiainen, Erkki, Brand, Stefan-Martin, Kutalik, Zoltán, Lo, Ken Sin, Staessen, Jan A, Wang, Thomas J, Burton, Paul R, Artigas, Maria Soler, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K, Rudock, Megan E, Lobbens, Stéphane, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margus, Kinra, Sanjay, Prabhakaran, Dorairajan, Tripathy, Vikal, Lorbeer, Roberto, Langefeld, Carl D, Rosengren, Annika, Thelle, Dag S, Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, Salako, Tunde, Iwai, Naoharu, Lu, Yingchang, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thomas, Wichmann, H-Erich, Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, James, Sehmi, Joban S, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Raffel, Leslie J, Yao, Jie, O'Donnell, Chris, Schwartz, Stephen M, Ikram, M Arfan, Longstreth, W. T., Mosley, Thomas H, Seshadri, Sudha, Mahajan, Anubha, Shrine, Nick R G, Wain, Louise V, Morken, Mario A, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A, Rasheed, Asif, Goel, Anuj, Watkins, Hugh, Bakker, Stephan J L, van Gilst, Wiek H, Janipalli, Charles S, Mani, K Radha, Yajnik, Chittaranjan S, McLachlan, Stela, Mattace-Raso, Francesco U S, Oostra, Ben A, Demirkan, Ayse, Lakatta, Edward G, Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J, Menni, Cristina, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Ong, Rick Twee-Hee, Dörr, Marcus, Kroemer, Heyo K, Völker, Uwe, Völzke, Henry, Galan, Pilar, Merger, Sigrun, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Zhai, Guangju, Meschia, James F, Nalls, Michael A, Sharma, Pankaj, Terzic, Janos, Kumar, M J Kranthi, Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E, Fowkes, F Gerald R, Charchar, Fadi J, Guo, Xiuqing, Milani, Lili, Rotimi, Charles, Bots, Michiel L, Brand, Eva, Samani, Nilesh J, Polasek, 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EN., Warrington, NM., Alavere, H., Barroso, I., Berenson, GS., Blackburn, H., Busonero, F., Chen, W., Couper, D., Easton, DF., Eriksson, J., Foroud, T., Geller, F., Hernandez, DG., Kilpeläinen, TO., Li, S., Melbye, M., Murray, JC., Murray, SS., Nelis, M., Ness, AR., Northstone, K., Peacock, M., Pennell, CE., Pharoah, P., Rafnar, T., Rice, JP., Ring, SM., Schork, NJ., Segrè, AV., Sovio, U., Srinivasan, SR., Tammesoo, ML., Tyrer, J., van Meurs JB., Weedon, MN., Wichmann, H., Young, L., Bierut, LJ., Boyd, HA., Econs, MJ., Van T'Hooft, Ferdinand M., Njølstad, Inger, Abecasis, Gonçalo R., Barroso, Inɥ, The MIGEN Consortium, Investigator, Casari, GIORGIO NEVIO, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Landsteiner Laboratory, Clinical Haematology, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Locke, A, Kahali, B, Berndt, S, Justice, A, Pers, T, Day, F, Powell, C, Vedantam, S, Buchkovich, M, Yang, J, Croteau-Chonka, D, Esko, T, Fall, T, Ferreira, T, Gustafsson, S, Kutalik, Z, Luan, J, Magi, R, Randall, J, Winkler, T, Wood, A, Workalemahu, T, Faul, J, Smith, J, Zhao, J, Zhao, W, Chen, J, Fehrmann, R, Hedman, A, Karjalainen, J, Schmidt, E, Absher, D, Amin, N, Anderson, D, Beekman, M, Bolton, J, Bragg-Gresham, J, Buyske, S, Demirkan, A, Deng, G, Ehret, G, Feenstra, B, Feitosa, M, Fischer, K, Goel, A, Gong, J, Jackson, A, Kanoni, S, Kleber, M, Kristiansson, K, Lim, U, Lotay, V, 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Investigators, The MuTHER Consortium, The MIGen Consortium, The PAGE Consortium, The ReproGen Consortium, The GENIE Consortium, The International Endogene Consortium, Berndt, Sonja I, Justice, Anne E, Hyppönen, Elina Tuulikki, Epidemiology and Data Science, NCA - Neurobiology of mental health, and EMGO - Lifestyle, overweight and diabetes
Subjects: Male, LOCI, Genome-wide association study, Continental Population Groups/genetics, VARIANTS, Body Mass Index, Insulin Secretion, Insulin, Age Factor, Adiposity, ddc:616, Adipogenesis, Genetic Predisposition to Disease/genetics, Synapse, 3. Good health, Continental Population Group, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], GENOME-WIDE ASSOCIATIONPROVIDES INSIGHTSGLYCEMIC TRAITSLOCIMETAANALYSISVARIANTSINDIVIDUALSHIPPOCAMPALARCHITECTURETOPIRAMATE, ddc:500, Adipogenesis/genetics, Single Nucleotide/genetics, Age Factors, Continental Population Groups, Energy Metabolism, Europe, Female, Genetic Predisposition to Disease, Glutamic Acid, Humans, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Synapses, Genome-Wide Association Study, Multidisciplinary, genetics [Adiposity], Human, Socio-culturale, genetics [Energy Metabolism], ta3111, genetic, body mass index, obesity, SDG 3 - Good Health and Well-being, GLYCEMIC TRAITS, genetics [Continental Population Groups], Genetic variability, Polymorphism, GENOME-WIDE ASSOCIATION, genetics [Adipogenesis], METAANALYSIS, Genetic association, Adipogenesi, genetics [Quantitative Trait Loci], ta1184, metabolism [Glutamic Acid], ta1182, PATHWAYS, metabolism [Synapses], ta3121, medicine.disease, metabolism [Insulin], Adiposity/genetics, Clinical Medicine, Quantitative Trait Loci/genetics, Body mass index, HUMAN HEIGHT, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Synapses/metabolism, Medizin, Obesity/genetics, Bioinformatics, genetic basis, Obesity/metabolism, genetics [Obesity], body mass index (BMI), genetics [Genetic Predisposition to Disease], ethnology [Europe], 2. Zero hunger, Genetics, ARCHITECTURE, Genetics of obesity, Medicine (all), Single Nucleotide, Polymorphism, Single Nucleotide/genetics, Insulin/metabolism/secretion, Glutamic Acid/metabolism, genetics [Polymorphism, Single Nucleotide], EXPRESSION, Insulin/metabolism, PROVIDES INSIGHTS, genetics [Racial Groups], Biology, Obesity/genetics/metabolism, Europe/ethnology, metabolism [Obesity], Mendelian randomization, medicine, Energy Metabolism/genetics, body mass, genetic analysis, obesity, Klinisk medicin
Abstract: Item does not contain fulltext Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for approximately 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
Published: 2015

30. Identification of a dominant MYH11 causal variant in chronic intestinal pseudo‐obstruction: Results of whole‐exome sequencing.

Author: Dong, Weilai, Baldwin, Clinton, Choi, Jungmin, Milunsky, Jeff M., Zhang, Junhui, Bilguvar, Kaya, Lifton, Richard P., and Milunsky, Aubrey
Subjects: MYOSIN, SMOOTH muscle contraction, RECESSIVE genes, EXTENDED families, SMOOTH muscle, NEMALINE myopathy, GASTROINTESTINAL system, DYSPLASIA
Abstract: Chronic Intestinal Pseudo‐Obstruction (CIPO) is a rare gastrointestinal disorder, which affects the smooth muscle contractions of the gastrointestinal tract. Dominant mutations in the smooth muscle actin gene, ACTG2, accounts for 44%‐50% of CIPO patients. Other recessive or X‐linked genes, including MYLK, LMOD1, RAD21, MYH11, MYL9, and FLNA were reported in single cases. In this study, we used Whole‐Exome Sequencing (WES) to study 23 independent CIPO families including one extended family with 13 affected members. A dominantly inherited rare mutation, c.5819delC (p.Pro1940HisfsTer91), in the smooth muscle myosin gene, MYH11, was found in the extended family, shared by 7 affected family members but not by 3 unaffected family members with available DNA, suggesting a high probability of genetic linkage. Gene burden analysis indicates that additional genes, COL4A1, FBLN1 and HK2, may be associated with the disease. This study expanded our understanding of CIPO etiology and provided additional genetic evidence to physicians and genetic counselors for CIPO diagnosis. [ABSTRACT FROM AUTHOR]
Published: 2019
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31. New genetic loci link adipose and insulin biology to body fat distribution

Author: Shungin, Dmitry, Winkler, Thomas W, Workalemahu, Tsegaselassie, Hartman, Catharina A, Duncan, Emma L, Ntzani, Evangelia E, Oei, Ling, Albagha, Omar M E, Amin, Najaf, Kemp, John P, Koller, Daniel L, Li, Guo, Liu, Ching-Ti, Minster, Ryan L, Hassinen, Maija, Moayyeri, Alireza, Vandenput, Liesbeth, Willner, Dana, Xiao, Su-Mei, Yerges-Armstrong, Laura M, Zheng, Hou-Feng, Alonso, Nerea, Eriksson, Joel, Kammerer, Candace M, Kaptoge, Stephen K, Hayward, Caroline, Leo, Paul J, Thorleifsson, Gudmar, Wilson, Scott G, Wilson, James F, Aalto, Ville, Alen, Markku, Aragaki, Aaron K, Aspelund, Thor, Center, Jacqueline R, Dailiana, Zoe, Heikkilä, Kauko, Duggan, David J, Garcia, Melissa, Garcia-Giralt, Natàlia, Giroux, Sylvie, Hallmans, Göran, Hocking, Lynne J, Husted, Lise Bjerre, Jameson, Karen A, Khusainova, Rita, Kim, Ghi Su, Herzig, Karl-Heinz, Kooperberg, Charles, Koromila, Theodora, Kruk, Marcin, Laaksonen, Marika, Lacroix, Andrea Z, Lee, Seung Hun, Leung, Ping C, Lewis, Joshua R, Masi, Laura, Mencej-Bedrac, Simona, Helmer, Quinta, Nguyen, Tuan V, Nogues, Xavier, Patel, Millan S, Prezelj, Janez, Rose, Lynda M, Scollen, Serena, Siggeirsdottir, Kristin, Smith, Albert V, Svensson, Olle, Trompet, Stella, Hillege, Hans L, Trummer, Olivia, van Schoor, Natasja M, Woo, Jean, Zhu, Kun, Balcells, Susana, Brandi, Maria Luisa, Buckley, Brendan M, Cheng, Sulin, Christiansen, Claus, Cooper, Cyrus, Holmen, Oddgeir, Dedoussis, George, Ford, Ian, Frost, Morten, Goltzman, David, González-Macías, Jesús, Kähönen, Mika, Karlsson, Magnus, Khusnutdinova, Elza, Koh, Jung-Min, Kollia, Panagoula, Hunt, Steven C, Langdahl, Bente Lomholt, Leslie, William D, Lips, Paul, Ljunggren, Östen, Lorenc, Roman S, Marc, Janja, Mellström, Dan, Obermayer-Pietsch, Barbara, Olmos, José M, Pettersson-Kymmer, Ulrika, Isaacs, Aaron, Reid, David M, Riancho, José A, Ridker, Paul M, Rousseau, François, Slagboom, P Eline, Tang, Nelson L S, Urreizti, Roser, Van Hul, Wim, Viikari, Jorma, Zarrabeitia, María T, Wu, 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NourEddine, Van Vliet-Ostaptchouk, Jana V, Hager, Jörg, Hunt, Sarah E, Kang, Hyun M, Kessler, Thorsten, Knowles, Joshua W, Kolovou, Genovefa, Langford, Cordelia, Lokki, Marja-Liisa, Lundmark, Anders, Maouche, Seraya, Nikus, Kjell, Rayner, N William, Rosinger, Silke, Rubin, Diana, Rumpf, Moritz P, Schäfer, Arne, Sivananthan, Mohan, Stewart, Alexandre F R, Tan, Sian-Tsung, Thorgeirsson, Gudmundur, van der Schoot, C Ellen, Wagner, Peter J, Wells, George A, Wild, Philipp S, Ärnlöv, Johan, Basart, Hanneke, Cambien, Francois, Cupples, Adrienne L, Arscott, Gillian M, Diemert, Patrick, Evans, Alun, Ferrario, Marco M, Gauguier, Dominique, Go, Alan S, Goodall, Alison H, Gudnason, Villi, Hazen, Stanley L, Jang, Yangsoo, Kim, Hyo-Soo, Laaksonen, Reijo, Lee, Ji-Young, Ouwehand, Willem H, Parish, Sarah, Park, Jeong E, Bellis, Claire, Schadt, Eric, Shah, Svati H, Stark, Klaus, Trégouët, David-Alexandre, Virtamo, Jarmo, Bennett, Amanda J, Wareham, Nicholas, Zimmermann, Martina E, Nieminen, Markku S, Hengstenberg, Christian, Berne, Christian, Zalloua, Pierre A, Blankenberg, Stefan S, Pers, Tune H, Blüher, Matthias, O'Donnell, Christopher, Roberts, Robert, Schunkert, Heribert, Garnaas, Maija, Böger, Carsten A, Bonnet, Fabrice, Tin, Adrienne, Taliun, Daniel, Li, Man, Gao, Xiaoyi, Gorski, Mathias, Yang, Qiong, Hundertmark, Claudia, Böttcher, Yvonne, Foster, Meredith C, O'Seaghdha, Conall M, Struchalin, Maksim, Gierman, Hinco J, Feitosa, Mary, Atkinson, Elizabeth J, Carba, Delia B, Chouraki, Vincent, Holliday, Elizabeth G, Sorice, Rossella, Kutalik, Zoltan, Deshmukh, Harshal, Chu, Audrey Y, Murgia, Federico, Caspersen, Ida H, Imboden, Medea, Kollerits, Barbara, Schmidt, Helena, Cavalieri, Margherita, Rao, Madhumathi, de Andrade, Mariza, Turner, Stephen T, Ding, Jingzhong, Daw, E Warwick, Freedman, Barry I, Wichmann, H -Erich, Minelli, Cosetta, Wheeler, Heather E, Deelen, Joris, Zaboli, Ghazal, Ellinghaus, David, Nöthlings, Ute, Jacobs, Gunnar, Biffar, Reiner, Endlich, Karlhans, Nauck, 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Surdulescu, G., Travers, ME., Tsaprouni, L., Tsoka, S., Wilk, A., Matise, T., Buyske, S., Higashio, J., Williams, R., Nato, A., Ambite, JL., Deelman, E., Manolio, T., Hindorff, L., Heiss, G., Taylor, K., Avery, C., Graff, M., Lin, D., Quibrera, M., Cochran, B., Kao, L., Umans, J., Cole, S., MacCluer, J., Person, S., Pankow, J., Gross, M., Fornage, M., Durda, P., Jenny, N., Patsy, B., Arnold, A., Buzkova, P., Crawford, D., Haines, J., Murdock, D., Glenn, K., Brown-Gentry, K., Thornton-Wells, T., Dumitrescu, L., Jeff, J., Bush, WS., Mitchell, SL., Goodloe, R., Wilson, S., Boston, J., Malinowski, J., Restrepo, N., Oetjens, M., Fowke, J., Zheng, W., Spencer, K., Ritchie, M., Pendergrass, S., Le Marchand£££Loïc£££ L., Wilkens, L., Park, L., Tiirikainen, M., Kolonel, L., Lim, U., Cheng, I., Wang, H., Shohet, R., Haiman, C., Stram, D., Henderson, B., Monroe, K., Schumacher, F., Peters, U., Anderson, G., Carlson, C., Prentice, R., LaCroix, A., Wu, C., Carty, C., Gong, J., Rosse, S., Young, A., Haessler, J., Kocarnik, J., Lin, Y., Jackson, R., Duggan, D., Kuller, L., Stolk, L., He, C., Sulem, P., Barbalic, M., Broer, L., Byrne, EM., Gudbjartsson, DF., McArdle, PF., Porcu, E., van Wingerden, S., Zhuang, W., Albrecht, E., Alizadeh, BZ., Lauc, LB., Broekmans, FJ., Burri, A., Chanock, SJ., Chen, C., Corre, T., Coviello, AD., d'Adamo, P., Davies, G., Deary, IJ., Ebrahim, S., Fauser, BC., Ferreli, L., Folsom, AR., Garcia, ME., Hall, P., Haller, T., Hankinson, SE., Hass, M., Heath, AC., Janssens, AC., Keyzer, J., Lahti, J., Lai, S., Laisk, T., Laven, JS., Liu, J., Lopez, LM., Louwers, YV., Marongiu, M., Klaric, IM., Masciullo, C., McKnight, B., Medland, SE., Melzer, D., Newman, AB., Paré, G., Peeters, PH., Plump, AS., Pop, VJ., Räikkönen, K., Salumets, A., Smith, JA., Stacey, SN., Starr, JM., Stathopoulou, MG., Tenesa, A., Thorand, B., Tryggvadottir, L., Tsui, K., van Dam RM., van Gils CH., van Nierop, P., Vink, JM., Voorhuis, M., Wallaschofski, H., Widen, E., Wijnands-van Gent CJ., Zgaga, L., Zygmunt, M., Arnold, AM., Buring, JE., Crisponi, L., Demerath, EW., Hunter, DJ., Schlessinger, D., Murray, A., Murabito, JM., Visser, JA., Lunetta, KL., Elks, CE., Cousminer, DL., Feenstra, B., Lin, P., van Wingerden SW., Smith, EN., Warrington, NM., Alavere, H., Barroso, I., Berenson, GS., Blackburn, H., Busonero, F., Chen, W., Couper, D., Easton, DF., Foroud, T., Geller, F., Hernandez, DG., Kilpeläinen, TO., Li, S., Melbye, M., Murray, JC., Murray, SS., Nelis, M., Ness, AR., Northstone, K., Pennell, CE., Pharoah, P., Rafnar, T., Rice, JP., Ring, SM., Schork, NJ., Segrè, AV., Sovio, U., Srinivasan, SR., Tammesoo, ML., Tyrer, J., Weedon, MN., Wichmann, H., Young, L., Zhuang, WV., Bierut, LJ., Boyd, HA., Department of Clinical Sciences, Lund University [Lund], Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Department of Odontology, Umeå University, Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Sciences, Center for Biological Sequence Analysis [Lyngby], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Laboratory of Image Science and Technology [Nanjing] (LIST), Southeast University [Jiangsu]-School of Computer Science and Engineering, Limnology, Ecology, Estonian Genome and Medicine, University of Tartu, Institute of Molecular and Cell Biology, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Institute of Medical Informatics, Biometry and Epidemiology, Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetic Epidemiology Unit, 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(INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Department of Pharmacy Sciences, Creighton University Medical Center, Medical Department III, Universität Leipzig, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Department of Epidemiology, Erasmus Medical Centre, Netherlands Genomics Initiative (NGI), Netherlands Genomics Initiative, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Department of Public Health and Clinical Medicine, Medstar Research Institute, Genetics and Pathology, Finnish Institute of Occupational Health, Epidemiology, University Medical Centre Groningen, Departments of Microbiology & Molecular Genetics and Molecular Biology & Biochemistry, University of California [Irvine] (UC Irvine), Department of Odontology, Cariology, Institute of Human Genetics, Helmholtz Zentrum München = German Research Center for Environmental Health, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Division of Cardiology, Geneva University Hospital (HUG), Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Physics, Indian Institute of Technology Kanpur (IIT Kanpur), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Anaesthesia and Intensive care, Royal Aberdeen Childrens Hospital, UCL Institute of neurology, UCL Institute of Neurology, Human Genetics, The Wellcome Trust Sanger Institute [Cambridge], 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= University of Helsinki, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, Department of Pediatrics, Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Department of Public Health, South Ostrobothnia Central Hospital, Department of Clinical and Preventive Medicine, Danube-University Krems, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Institute of Public Health and Clinical Nutrition, University of Eastern Finland, MRC epidemiology Unit, Institute of Epidemiology, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Oncology, Queensland Brain Institute, University of Queensland [Brisbane], Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, 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(BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Endocrinology and Metabolism, The Churchill Hospital-Oxford Centre for Diabetes, Landsteiner Laboratory, Clinical Haematology, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Lund University Diabetes Centre-Lund University [Lund], Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers, Technical University of Denmark [Lyngby] (DTU), Université de Lausanne (UNIL), Universität Duisburg-Essen [Essen], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), University of California [Berkeley], University of California-University of California, Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche 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Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Helmholtz-Zentrum München (HZM), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Internal Medicine, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Medical Informatics, Obstetrics & Gynecology, Lund University [Lund]-Lund University Diabetes Centre, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institute of Medicine-University of Gothenburg (GU), Signalisation et Transports Ioniques Membranaires ( STIM ), Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS ), Technical University of Denmark [Lyngby] ( DTU ), Laboratory of Image Science and Technology [Nanjing] ( LIST ), Department of Medical Epidemiology and Biostatistics ( MEB ), University of Lausanne, Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Erasmus MC, Space Sciences Laboratory [Berkeley] ( SSL ), Génomique Intégrative et Modélisation des Maladies Métaboliques ( EGID ), Université de Lille-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), University of Leipzig, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institute of Epidemiology [Neuherberg] ( EPI ), University of California [Irvine] ( UCI ), Génétique des maladies multifactorielles ( GMM ), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Geneva University Hospital ( HUG ), Bonn Universität [Bonn], Indian Institute of Technology Kanpur ( IIT Kanpur ), The University of North Carolina at Chapel Hill, Université de Bonn, Wellcome Trust Sanger Institute, Harvard University School of Public Health, Czech Academy of Sciences [Prague] ( ASCR ), deCODE genetics, University of Groningen [Groningen]-University Medical Center Groningen-Beatrix Children's Hospital-Groningen Research Institute for Asthma and COPD, Yale School of Medicine, National Heart and Lung Institute ( NHLI ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, University Medical Center Groningen, University of Cambridge [UK] ( CAM ), Wellcome Trust Centre for Human Genetics, University of Pisa [Pisa], University of Cambridge [UK] ( CAM ) -Institute of Metabolic Science, German Research Center for Environmental Health-Helmholtz-Zentrum München ( HZM ), University of Otago, University of Greifswald, University College of London [London] ( UCL ), National Institute for Health and Welfare, Queen's University [Belfast] ( QUB ), University of Hawaii at Manoa ( UHM ), University of Gothenburg ( GU ) -Institute of Medicine, Recherches en Psychopathologie, nouveaux symptômes et lien social ( EA 4050 ), Université de Poitiers-Université de Brest ( UBO ) -Université Catholique de l'Ouest-Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Institut de biologie de Lille - IBL ( IBLI ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University Medicine Greifswald,-HELIOS Hospital Stralsund, Finland Institute for Molecular Medicine ( FIMM ), Georgia Prevention Institute, Netherlands Consortium for Healthy Aging, Helmholtz-Zentrum München ( HZM ), National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Massachusetts General Hospital, Children's Hospital, Boston, Broad Institute, Cambridge, MA, The University of North Carolina at Chapel Hill-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Shungin D, Winkler TW, Adipogen, Consortium, Cardiogramplusc4d, Consortium, Ckdgen, Consortium, Gefos, Consortium, Genie, Consortium, Glgc, Icbp, International, Endogene Consortium, Lifelines, Cohort Study, Magic, Investigator, Muther, Consortium, Consortium, Page, ReproGen Consortium, Amouyel P, D'Adamo, ADAMO PIO, Gasparini, Paolo, Shungin, Dmitry, Winkler, Thomas W, Croteau-Chonka, Damien C, Ferreira, Teresa, Hypponen, Elina, Mohlke, Karen L, ADIPOGEN Consortium, Int Endogene Consortium, Lee Kong Chian School of Medicine (LKCMedicine), Epidemiologie, RS: CARIM - R3.02 - Hypertension and target organ damage, Université de Tours-Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Shungin, D, Winkler, T, Croteau Chonka, D, Ferreira, T, Locke, A, Mägi, R, Strawbridge, R, Pers, T, Fischer, K, Justice, A, Workalemahu, T, Wu, J, Buchkovich, M, Heard Costa, N, Roman, T, Drong, A, Song, C, Gustafsson, S, Day, F, Esko, T, Fall, T, Kutalik, Z, Luan, J, Randall, J, Scherag, A, Vedantam, S, Wood, A, Chen, J, Fehrmann, R, Karjalainen, J, Kahali, B, Liu, C, Schmidt, E, Absher, D, Amin, N, Anderson, D, Beekman, M, Bragg Gresham, J, Buyske, S, Demirkan, A, Ehret, G, Feitosa, M, Goel, A, Jackson, A, Johnson, T, Kleber, M, Kristiansson, K, Mangino, M, Leach, I, Medina Gomez, C, Palmer, C, Pasko, D, Pechlivanis, S, Peters, M, Prokopenko, I, Stanca'Kova', A, Sung, Y, Tanaka, T, Teumer, A, Van Vliet Ostaptchouk, J, Yengo, L, Zhang, W, Albrecht, E, Ärnlöv, J, Arscott, G, Bandinelli, S, Barrett, A, Bellis, C, Bennett, A, Berne, C, Blüher, M, Böhringer, S, Bonnet, F, Böttcher, Y, Bruinenberg, M, Carba, D, Caspersen, I, Clarke, R, Daw, E, Deelen, J, Deelman, E, Delgado, G, Doney, A, Eklund, N, Erdos, M, Estrada, K, Eury, E, Friedrich, N, Garcia, M, Giedraitis, V, Gigante, B, Go, A, Golay, A, Grallert, H, Grammer, T, Gräsler, J, Grewal, J, Groves, C, Haller, T, Hallmans, G, Hartman, C, Hassinen, M, Hayward, C, Heikkilä, K, Herzig, K, Helmer, Q, Hillege, H, Holmen, O, Hunt, S, Isaacs, A, Ittermann, T, James, A, Johansson, I, Juliusdottir, T, Kalafati, I, Kinnunen, L, Koenig, W, Kooner, I, Kratzer, W, Lamina, C, Leander, K, Lee, N, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Mach, F, Magnusson, P, Mahajan, A, Mcardle, W, Menni, C, Merger, S, Mihailov, E, Milani, L, Mills, R, Moayyeri, A, Monda, K, Mooijaart, S, Mühleisen, T, Mulas, A, Müller, G, Müller Nurasyid, M, Nagaraja, R, Nalls, M, Narisu, N, Glorioso, N, Nolte, I, Olden, M, Rayner, N, Renstrom, F, Ried, J, Robertson, N, Rose, L, Sanna, S, Scharnagl, H, Scholtens, S, Sennblad, B, Seufferlein, T, Sitlani, C, Smith, A, Stirrups, K, Stringham, H, Sundström, J, Swertz, M, Swift, A, Syvänen, A, Tayo, B, Thorand, B, Thorleifsson, G, Tomaschitz, A, Troffa, C, Van Oort, F, Verweij, N, Vonk, J, Waite, L, Wennauer, R, Wilsgaard, T, Wojczynski, M, Wong, A, Zhang, Q, Zhao, J, Brennan, E, Choi, M, Eriksson, P, Folkersen, L, Franco Cereceda, A, Gharavi, A, Hedman, A, Hivert, M, Huang, J, Kanoni, S, Karpe, F, Keildson, S, Kiryluk, K, Liang, L, Lifton, R, Ma, B, Mcknight, A, Mcpherson, R, Metspalu, A, 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Brown Gentry, K, Thornton Wells, T, Dumitrescu, L, Jeff, J, Bush, W, Mitchell, S, Goodloe, R, Boston, J, Malinowski, J, Restrepo, N, Oetjens, M, Fowke, J, Zheng, W, Spencer, K, Pendergrass, S, Wilkens, L, Park, L, Tiirikainen, M, Kolonel, L, Lim, U, Cheng, I, Wang, H, Shohet, R, Stram, D, Henderson, B, Monroe, K, Schumacher, F, Anderson, G, Carlson, C, Prentice, R, Wu, C, Carty, C, Gong, J, Rosse, S, Young, A, Haessler, J, Kocarnik, J, Lin, Y, Kuller, L, He, C, Sulem, P, Barbalic, M, Broer, L, Byrne, E, Gudbjartsson, D, Mcardle, P, Porcu, E, van Wingerden, S, Zhuang, W, Lauc, L, Broekmans, F, Burri, A, Chanock, S, Chen, C, Corre, T, Coviello, A, D'Adamo, P, Davies, G, Deary, I, Ebrahim, S, Fauser, B, Ferreli, L, Folsom, A, Hall, P, Hankinson, S, Hass, M, Heath, A, Janssens, A, Keyzer, J, Lahti, J, Lai, S, Laisk, T, Laven, J, Liu, J, Lopez, L, Louwers, Y, Marongiu, M, Klaric, I, Masciullo, C, Medland, S, Melzer, D, Newman, A, Paré, G, Peeters, P, Pop, V, Räikkönen, K, Salumets, A, Smith, J, Stacey, S, Starr, J, Stathopoulou, M, Tenesa, A, Tryggvadottir, L, Tsui, K, van Dam, R, van Gils, C, van Nierop, P, Vink, J, Voorhuis, M, Wallaschofski, H, Widen, E, Wijnands van Gent, C, Zgaga, L, Zygmunt, M, Buring, J, Crisponi, L, Demerath, E, Murray, A, Visser, J, Lunetta, K, Elks, C, Cousminer, D, Feenstra, B, Lin, P, Smith, E, Warrington, N, Alavere, H, Berenson, G, Blackburn, H, Busonero, F, Chen, W, Easton, D, Foroud, T, Geller, F, Kilpeläinen, T, Li, S, Melbye, M, Murray, J, Murray, S, Ness, A, Northstone, K, Pennell, C, Pharoah, P, Rafnar, T, Rice, J, Ring, S, Schork, N, Segrè, A, Sovio, U, Srinivasan, S, Tammesoo, M, Tyrer, J, Weedon, M, Young, L, Bierut, L, Boyd, H, Psychiatry, NCA - Neurobiology of mental health, and EMGO - Lifestyle, overweight and diabetes
Subjects: Adipose Tissue/metabolism, Male, genetic association, subcutaneous fat, Transcription, Genetic, Adipocytes, Adipogenesis, Adipose Tissue, Age Factors, Body Mass Index, Continental Population Groups, Epigenesis, Genetic, Europe, Female, Genome, Human, Humans, Insulin, Insulin Resistance, Models, Biological, Neovascularization, Physiologic, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Sex Characteristics, Waist-Hip Ratio, Body Fat Distribution, Genome-Wide Association Study, Multidisciplinary, Insulin Resistance/genetics, Genome-wide association study, Continental Population Groups/genetics, genetic analysis, heritability, gene cluster, Science::Biological sciences::Human anatomy and physiology [DRNTU], 0302 clinical medicine, high density lipoprotein cholesterol, Models, genetics [Insulin Resistance], histone modification, Age Factor, insulin receptor, 0303 health sciences, Adipocyte, Human/genetics, CARDIOGRAMplusC4D Consortium, ADIPOGENIC DIFFERENTIATION, genetic correlation, body fat, Continental Population Group, priority journal, 5 trisphosphate 3 phosphatase, GEFOS Consortium, meta analysis (topic), Science & Technology - Other Topics, ddc:500, transcription regulation, Adipogenesis/genetics, Single Nucleotide/genetics, Human, medicine.medical_specialty, Waist, phosphatidylinositol 3, European, ta3111, genetic regulation, Article, developmental biology, 03 medical and health sciences, MAGIC Investigators, transcription initiation site, SDG 3 - Good Health and Well-being, Genetic, genomics, GLYCEMIC TRAITS, genetics [Continental Population Groups], Polymorphism, GENOME-WIDE ASSOCIATION, Physiologic, genetics [Adipogenesis], Adipocytes/metabolism, Europe/ethnology, Genome, Human/genetics, Insulin/metabolism, Neovascularization, Physiologic/genetics, Obesity/genetics, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Transcription, Genetic/genetics, Genetic/genetics, Adipogenesi, Science & Technology, adiponectin, [ SDV ] Life Sciences [q-bio], vasculotropin, genetics [Quantitative Trait Loci], ta1184, Racial Groups, ta1182, gene mapping, ta3121, triacylglycerol blood level, medicine.disease, Biological, major clinical study, amino acid sequence, metabolism [Insulin], Endocrinology, metabolism [Adipocytes], genetic loci, insulin, body fat, GLGC, International Endogene Consortium, metabolism [Adipose Tissue], Body mass index, HUMAN HEIGHT, Epigenesis, LifeLines Cohort Study, ReproGen Consortium, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, tissue level, Physiologic/genetics, [SDV]Life Sciences [q-bio], Medizin, Adipose tissue, low density lipoprotein cholesterol, PAGE Consortium, COMMON SNPS, angiogenesis, Waist–hip ratio, genetics [Obesity], MESH: Adipocytes/metabolism Adipogenesis/genetics Adipose Tissue/metabolism* Age Factors Body Fat Distribution* Body Mass Index Continental Population Groups/genetics Epigenesis, Genetic Europe/ethnology Female Genome, Human/genetics Genome-Wide Association Study* Humans Insulin/metabolism* Insulin Resistance/genetics Male Models, Biological Neovascularization, Physiologic/genetics Obesity/genetics Polymorphism, Single Nucleotide/genetics Quantitative Trait Loci/genetics* Sex Characteristics Transcription, Genetic/genetics Waist-Hip Ratio, single nucleotide polymorphism, fat, genetic variability, molecular biology, body mass index (BMI), ethnology [Europe], peroxisome proliferator activated receptor, 2. Zero hunger, Genetics, Genome, Single Nucleotide, waist circumference, insulin, phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase, triacylglycerol, vasculotropin, developmental biology, gene expression, genome, numerical model, adipocyte, adipose tissue, body fat distribution, body mass, female, gene locus, gene structure, hip circumference, human, insulin resistance, lipoprotein blood level, male, obesity, protein protein interaction, sex difference, waist hip ratio, Multidisciplinary Sciences, genetics [Transcription, Genetic], genetics [Polymorphism, Single Nucleotide], ADIPOGen Consortium, genetics [Neovascularization, Physiologic], Transcription, SUSCEPTIBILITY LOCI, General Science & Technology, ICBP, 030209 endocrinology & metabolism, Biology, adipocyte, MESH : Adipocytes/metabolism Adipogenesis/genetics Adipose Tissue/metabolism* Age Factors Body Fat Distribution* Body Mass Index Continental Population Groups/genetics Epigenesis, Genetic Europe/ethnology Female Genome, Human/genetics Genome-Wide Association Study* Humans Insulin/metabolism* Insulin Resistance/genetics Male Models, Biological Neovascularization, Physiologic/genetics Obesity/genetics Polymorphism, Single Nucleotide/genetics Quantitative Trait Loci/genetics* Sex Characteristics Transcription, Genetic/genetics Waist-Hip Ratio, MESENCHYMAL STEM-CELLS, GENIE Consortium, SEXUAL-DIMORPHISM, Insulin resistance, Internal medicine, medicine, genetics [Genome, Human], ABDOMINAL ADIPOSITY, Neovascularization, 030304 developmental biology, FALSE DISCOVERY, CKDGen Consortium, Sex Characteristic, MuTHER Consortium, numerical model
Abstract: Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P
Published: 2015

32. Recessive Inheritance of Congenital Hydrocephalus With Other Structural Brain Abnormalities Caused by Compound Heterozygous Mutations in ATP1A3.

Author: Allocco, August A., Jin, Sheng Chih, Duy, Phan Q., Furey, Charuta G., Zeng, Xue, Dong, Weilai, Nelson-Williams, Carol, Karimy, Jason K., DeSpenza, Tyrone, Hao, Le T., Reeves, Benjamin, Haider, Shozeb, Gunel, Murat, Lifton, Richard P., and Kahle, Kristopher T.
Subjects: BRAIN abnormalities, NEMALINE myopathy, NEURAL stem cells, HYDROCEPHALUS, ARNOLD-Chiari deformity, CORPUS callosum
Abstract: Background: ATP1A3 encodes the α3 subunit of the Na+/K+ ATPase, a fundamental ion-transporting enzyme. Primarily expressed in neurons, ATP1A3 is mutated in several autosomal dominant neurological diseases. To our knowledge, damaging recessive genotypes in ATP1A3 have never been associated with any human disease. Atp1a3 deficiency in zebrafish results in hydrocephalus; however, no known association exists between ATP1A3 and human congenital hydrocephalus (CH). Methods: We utilized whole-exome sequencing (WES), bioinformatics, and computational modeling to identify and characterize novel ATP1A3 mutations in a patient with CH. We performed immunohistochemical studies using mouse embryonic brain tissues to characterize Atp1a3 expression during brain development. Results: We identified two germline mutations in ATP1A3 (p. Arg19Cys and p.Arg463Cys), each of which was inherited from one of the patient's unaffected parents, in a single patient with severe obstructive CH due to aqueductal stenosis, along with open schizencephaly, type 1 Chiari malformation, and dysgenesis of the corpus callosum. Both mutations are predicted to be highly deleterious and impair protein stability. Immunohistochemical studies demonstrate robust Atp1a3 expression in neural stem cells (NSCs), differentiated neurons, and choroid plexus of the mouse embryonic brain. Conclusion: These data provide the first evidence of a recessive human phenotype associated with mutations in ATP1A3 , and implicate impaired Na+/K+ ATPase function in the pathogenesis of CH. [ABSTRACT FROM AUTHOR]
Published: 2019
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33. The Congenital Heart Disease Genetic Network Study: Cohort description.

Author: Hoang, Thanh T., Goldmuntz, Elizabeth, Roberts, Amy E., Chung, Wendy K., Kline, Jennie K., Deanfield, John E., Giardini, Alessandro, Aleman, Adolfo, Gelb, Bruce D., Mac Neal, Meghan, Jr.Porter, George A., Kim, Richard, Brueckner, Martina, Lifton, Richard P., Edman, Sharon, Woyciechowski, Stacy, Mitchell, Laura E., and Agopian, A. J.
Subjects: CONGENITAL heart disease, PHENOTYPES, GENOTYPES, MEDICAL records, COHORT analysis, GENETICS
Abstract: The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects) and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot) and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome). Cases with CHDs were recruited through ten sites, 2010–2014. Information on cases (N = 9,727) and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40%) or left ventricular outflow tract obstruction (21%). Across CHD types, there were significant differences (p<0.05) in the distribution of all four case characteristics (e.g., sex), four parental characteristics (e.g., maternal pregestational diabetes), and five neurodevelopmental outcomes (e.g., learning disabilities). Several characteristics (e.g., sex) were also significantly different across CHD subtypes. The PCGC cohort is one of the largest CHD cohorts available for the study of genetic determinants of risk and outcomes. The majority of cases do not have a genetic diagnosis. This description of the PCGC cohort, including differences across CHD types and subtypes, provides a reference work for investigators who are interested in collaborating with or using publically available resources from the PCGC. [ABSTRACT FROM AUTHOR]
Published: 2018
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34. A Genome-Wide Association Study to Identify Single-Nucleotide Polymorphisms for Acute Kidney Injury.

Author: Bixiao Zhao, Qiongshi Lu, Yuwei Cheng, Belcher, Justin M., Siew, Edward D., Leaf, David E., Body, Simon C., Fox, Amanda A., Waikar, Sushrut S., Collard, Charles D., Thiessen-Philbrook, Heather, Ikizler, T. Alp, Ware, Lorraine B., Edelstein, Charles L., Garg, Amit X., Murim Choi, Schaub, Jennifer A., Hongyu Zhao, Lifton, Richard P., and Parikh, Chirag R.
Subjects: ACUTE kidney failure, APOLIPOPROTEINS, CATASTROPHIC illness, DISEASE susceptibility, GENETIC polymorphisms, CARDIAC surgery, HIGH density lipoproteins, INTENSIVE care units, NONPARAMETRIC statistics, PROTEINS, RESEARCH funding, SURGICAL complications, CASE-control method, SEQUENCE analysis, GENOTYPES
Abstract: Rationale: Acute kidney injury is a common and severe complication of critical illness and cardiac surgery. Despite significant attempts at developing treatments, therapeutic advances to attenuate acute kidney injury and expedite recovery have largely failed.Objectives: Identifying genetic loci associated with increased risk of acute kidney injury may reveal novel pathways for therapeutic development.Methods: We conducted an exploratory genome-wide association study to identify single-nucleotide polymorphisms associated with genetic susceptibility to in-hospital acute kidney injury.Measurements and Main Results: We genotyped 609,508 single-nucleotide polymorphisms and performed genotype imputation in 760 acute kidney injury cases and 669 controls. We then evaluated polymorphisms that showed the strongest association with acute kidney injury in a replication patient population containing 206 cases with 1,406 controls. We observed an association between acute kidney injury and four single-nucleotide polymorphisms at two independent loci on metaanalysis of discovery and replication populations. These include rs62341639 (metaanalysis P = 2.48 × 10-7; odds ratio [OR], 0.64; 95% confidence interval [CI], 0.55-0.76) and rs62341657 (P = 3.26 × 10-7; OR, 0.65; 95% CI, 0.55-0.76) on chromosome 4 near APOL1-regulator IRF2, and rs9617814 (metaanalysis P = 3.81 × 10-6; OR, 0.70; 95% CI, 0.60-0.81) and rs10854554 (P = 6.53 × 10-7; OR, 0.67; 95% CI, 0.57-0.79) on chromosome 22 near acute kidney injury-related gene TBX1.Conclusions: Our findings reveal two genetic loci that are associated with acute kidney injury. Additional studies should be conducted to functionally evaluate these loci and to identify other common genetic variants contributing to acute kidney injury. [ABSTRACT FROM AUTHOR]
Published: 2017
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35. Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults.

Author: Seidelmann, Sara B., Smith, Emily, Subrahmanyan, Lakshman, Dykas, Daniel, Abou Ziki, Maen D., Azari, Bani, Hannah-Shmouni, Fady, Yuexin Jiang, Akar, Joseph G., Marieb, Mark, Jacoby, Daniel, Bale, Allen E., Lifton, Richard P., and Mani, Arya
Abstract: Background—With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The use of whole exome sequencing for clinical diagnosis, risk stratification, and management of inherited CVD has not been previously evaluated. Methods and Results—We analyzed the results of whole exome sequencing in first 200 adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with a success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels (P=0.04). Whole exome sequencing was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death, in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to the discovery of novel candidate genes in another 14% of the cases. Conclusions—Whole exome sequencing is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited CVDs, particularly for poorly defined cases of sudden cardiac death. By presenting novel candidate genes and their potential disease associations, we also provide evidence for the use of this genetic tool for the identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown CVD genes. [ABSTRACT FROM AUTHOR]
Published: 2017
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36. Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis.

Author: Jiang, Tingting, Shi, Weiwei, Wali, Vikram B., Pongor, Lőrinc S., Li, Charles, Lau, Rosanna, Győrffy, Balázs, Lifton, Richard P., Symmans, William F., Pusztai, Lajos, and Hatzis, Christos
Subjects: TRIPLE-negative breast cancer, BREAST tumors, ANTHRACYCLINES, TAXANES, CANCER chemotherapy, ANTINEOPLASTIC agents, HYDROCARBONS, DRUG resistance in cancer cells, GENOMES, LONGITUDINAL method, RESEARCH funding, GENOMICS, THERAPEUTICS
Abstract: Background: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients.Methods and Findings: We performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC) selected because they had either pCR (n = 18) or extensive residual disease (n = 11) after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144) and METABRIC (n = 278) cohorts serving as validation cohorts. Our analysis revealed that mutations in the AR- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MDACC cohort (pCR rate of 94.1% compared to 16.6% in tumors without mutations in AR/FOXA1 pathway, adjusted p = 0.02) and significantly better survival outcome in the TCGA TNBC cohort (log-rank test, p = 0.05). Combined analysis of DNA sequencing, DNA methylation, and RNA sequencing identified tumors of a distinct BRCA-deficient (BRCA-D) TNBC subtype characterized by low levels of wild-type BRCA1/2 expression. Patients with functionally BRCA-D tumors had significantly better survival with standard-of-care chemotherapy than patients whose tumors were not BRCA-D (log-rank test, p = 0.021), and they had significantly higher mutation burden (p < 0.001) and presented clonal neoantigens that were associated with increased immune cell activity. A transcriptional signature of BRCA-D TNBC tumors was independently validated to be significantly associated with improved survival in the METABRIC dataset (log-rank test, p = 0.009). As a retrospective study, limitations include the small size and potential selection bias in the discovery cohort.Conclusions: The comprehensive molecular analysis presented in this study directly links BRCA deficiency with increased clonal mutation burden and significantly enhanced chemosensitivity in TNBC and suggests that functional RNA-based BRCA deficiency needs to be further examined in TNBC. [ABSTRACT FROM AUTHOR]
Published: 2016
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37. Shifting patterns of genomic variation in the somatic evolution of papillary thyroid carcinoma.

Author: Rubinstein, Jill C., Brown, Taylor C., Christison-Lagay, Emily R., Yawei Zhang, Kunstman, John W., Juhlin, C. Christofer, Nelson-Williams, Carol, Goh, Gerald, Quinn, Courtney E., Callender, Glenda G., Udelsman, Robert, Lifton, Richard P., Korah, Reju, Carling, Tobias, and Zhang, Yawei
Subjects: THYROID cancer, SOMATIC mutation, PAPILLARY carcinoma, CARCINOGENESIS, NUCLEOTIDE sequencing, EXOMES, GENETIC polymorphisms, GENETICS, DISEASE risk factors, AGE distribution, CANCER, GENOMES, MOLECULAR structure, RESEARCH funding, THYROID gland tumors, SEQUENCE analysis
Abstract: Background: Cancer is increasingly understood to arise in the context of dynamically evolving genomes with continuously generated variants subject to selective pressures. Diverse mutations have been identified in papillary thyroid carcinoma (PTC), but unifying theories underlying genomic change are lacking. Applying a framework of somatic evolution, we sought to broaden understanding of the PTC genome through identification of global trends that help explain risk of tumorigenesis.Methods: Exome sequencing was performed on 53 PTC and matched adjacent non-tumor thyroid tissues (ANT). Single nucleotide substitution (SNS) signatures from each sample pair were divided into three subsets based on their presence in tumor, non-tumor thyroid, or both. Nine matched blood samples were sequenced and SNS signatures intersected with these three subsets. The intersected genomic signatures were used to define branch-points in the evolution of the tumor genome, distinguishing variants present in the tissues' common ancestor cells from those unique to each tissue type and therefore acquired after genomic divergence of the tumor, non-tumor, and blood samples.Results: Single nucleotide substitutions shared by the tumor and the non-tumor thyroid were dominated by C-to-T transitions, whereas those unique to either tissue type were enriched for C-to-A transversions encoding non-synonymous, predicted-deleterious variants. On average, SNSs of matched blood samples were 81 % identical to those shared by tumor and non-tumor thyroid, but only 12.5 % identical to those unique to either tissue. Older age and BRAF mutation were associated with increased SNS burden.Conclusions: The current study demonstrates novel patterns of genomic change in PTC, supporting a theory of somatic evolution in which the zygote's germline genome undergoes continuous remodeling to produce progressively differentiated, tissue-specific signatures. Late somatic events in thyroid tissue demonstrate shifted mutational spectra compared to earlier polymorphisms. These late events are enriched for predicted-deleterious variants, suggesting a mechanism of genomic instability in PTC tumorigenesis. [ABSTRACT FROM AUTHOR]
Published: 2016
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38. De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.

Author: Priest, James R., Osoegawa, Kazutoyo, Mohammed, Nebil, Nanda, Vivek, Kundu, Ramendra, Schultz, Kathleen, Lammer, Edward J., Girirajan, Santhosh, Scheetz, Todd, Waggott, Daryl, Haddad, Francois, Reddy, Sushma, Bernstein, Daniel, Burns, Trudy, Steimle, Jeffrey D., Yang, Xinan H., Moskowitz, Ivan P., Hurles, Matthew, Lifton, Richard P., and Nickerson, Debbie
Subjects: CONGENITAL heart disease, ATRIOVENTRICULAR node, ATRIAL septal defects, VENTRICULAR septal defects, LABORATORY mice
Abstract: Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk. [ABSTRACT FROM AUTHOR]
Published: 2016
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39. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation.

Author: Romberg, Neil, Kazmierczak, Barbara I, Lifton, Richard P, Al Moussawi, Khatoun, Nelson-Williams, Carol, Choi, Murim, Stiegler, Amy L, Boggon, Titus J, Loring, Erin, Overton, John, Meffre, Eric, Khokha, Mustafa K, Huttner, Anita J, West, Brian, and Podoltsev, Nikolai A
Subjects: IMMUNE system, CELL membranes, ENTEROCOLITIS, INFLAMMATION, IMMUNOLOGY of inflammation, GENETIC mutation, GENETICS
Abstract: Upon detection of pathogen-associated molecular patterns, innate immune receptors initiate inflammatory responses. These receptors include cytoplasmic NOD-like receptors (NLRs) whose stimulation recruits and proteolytically activates caspase-1 within the inflammasome, a multiprotein complex. Caspase-1 mediates the production of interleukin-1 family cytokines (IL1FCs), leading to fever and inflammatory cell death (pyroptosis). Mutations that constitutively activate these pathways underlie several autoinflammatory diseases with diverse clinical features. We describe a family with a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of autoinflammation. We show that the disease is caused by a de novo gain-of-function mutation in NLRC4 encoding a p.Val341Ala substitution in the HD1 domain of the protein that cosegregates with disease. Mutant NLRC4 causes constitutive IL1FC production and macrophage cell death. Infected macrophages from affected individuals are polarized toward pyroptosis and exhibit abnormal staining for inflammasome components. These findings identify and describe the cause of a life-threatening but treatable autoinflammatory disease that underscores the divergent roles of the NLRC4 inflammasome. [ABSTRACT FROM AUTHOR]
Published: 2014
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40. Rare deleterious mutations of the gene EFR3A in autism spectrum disorders.

Author: Gupta, Abha R., Pirruccello, Michelle, Feng Cheng, Hyo Jung Kang, Fernandez, Thomas V., Baskin, Jeremy M., Murim Choi, Li Liu, Ercan-Sencicek, Adife Gulhan, Murdoch, John D., Klei, Lambertus, Neale, Benjamin M., Franjic, Daniel, Daly, Mark J., Lifton, Richard P., De Camilli, Pietro, Hongyu Zhao, Šestan, Nenad, and State, Matthew W.
Subjects: AUTISM spectrum disorders, GENETIC mutation, PHOSPHOINOSITIDES, NUCLEOTIDE sequencing, SACCHAROMYCES cerevisiae, GENETICS
Abstract: Background Whole-exome sequencing studies in autism spectrum disorder (ASD) have identified de novo mutations in novel candidate genes, including the synaptic gene Eighty-five Requiring 3A (EFR3A). EFR3A is a critical component of a protein complex required for the synthesis of the phosphoinositide PtdIns4P, which has a variety of functions at the neural synapse. We hypothesized that deleterious mutations in EFR3A would be significantly associated with ASD. Methods We conducted a large case/control association study by deep resequencing and analysis of whole-exome data for coding and splice site variants in EFR3A. We determined the potential impact of these variants on protein structure and function by a variety of conservation measures and analysis of the Saccharomyces cerevisiae Efr3 crystal structure. We also analyzed the expression pattern of EFR3A in human brain tissue. Results Rare nonsynonymous mutations in EFR3A were more common among cases (16 / 2,196 = 0.73%) than matched controls (12 / 3,389 = 0.35%) and were statistically more common at conserved nucleotides based on an experiment-wide significance threshold (P = 0.0077, permutation test). Crystal structure analysis revealed that mutations likely to be deleterious were also statistically more common in cases than controls (P = 0.017, Fisher exact test). Furthermore, EFR3A is expressed in cortical neurons, including pyramidal neurons, during human fetal brain development in a pattern consistent with ASD-related genes, and it is strongly co-expressed (P < 2.2 × 10-16, Wilcoxon test) with a module of genes significantly associated with ASD. Conclusions Rare deleterious mutations in EFR3A were found to be associated with ASD using an experiment-wide significance threshold. Synaptic phosphoinositide metabolism was strongly implicated in syndromic forms of ASD. These data for EFR3A strengthen the evidence for the involvement of this pathway in idiopathic autism. [ABSTRACT FROM AUTHOR]
Published: 2014
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41. Evaluating potential for whole-genome studies in Kosrae, an isolated population in Micronesia.

Author: Bonnen, Penelope E., Pe'er, Itsik, Plenge, Robert M., Salit, Jackie, Lowe, Jennifer K., Shapero, Michael H., Lifton, Richard P., Breslow, Jan L., Daly, Mark J., Reich, David E., Jones, Keith W., Stoffel, Markus, Altshuler, David, and Friedman, Jeffrey M.
Subjects: GENOMES, GENOMICS, GENETICS, GENES, POPULATION, ISLANDS
Abstract: Whole-genome association studies are predicted to be especially powerful in isolated populations owing to increased linkage disequilibrium (LD) and decreased allelic diversity, but this possibility has not been empirically tested. We compared genome-wide data on 113,240 SNPs typed on 30 trios from the Pacific island of Kosrae to the same markers typed in the 270 samples from the International HapMap Project. The extent of LD is longer and haplotype diversity is lower in Kosrae than in the HapMap populations. More than 98% of Kosraen haplotypes are present in HapMap populations, indicating that HapMap will be useful for genetic studies on Kosrae. The long-range LD around common alleles and limited diversity result in improved efficiency in genetic studies in this population and augments the power to detect association of 'hidden SNPs'. [ABSTRACT FROM AUTHOR]
Published: 2006
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42. Clinical and Genetic Correlates of Serum Aldosterone in the Community: The Framingham Heart Study

Author: Kathiresan, Sekar, Larson, Martin G., Benjamin, Emelia J., Corey, Diane, Murabito, Joanne M., Fox, Caroline S., Wilson, Peter W.F., Rifai, Nader, Meigs, James B., Ricken, Gesa, Lifton, Richard P., Levy, Daniel, and Vasan, Ramachandran S.
Subjects: ALDOSTERONE, SERUM, DISEASE risk factors, GENETIC polymorphisms
Abstract: Background: We investigated the environmental and genetic sources of interindividual variability in serum aldosterone level in a large, community-based sample. Methods: We examined the relation of serum aldosterone to vascular risk factors, urine sodium, and candidate single nucleotide polymorphisms in 2891 Framingham Offspring Study participants (53.2% women, mean age 59 years) using multivariable linear regression. Multivariable logistic regression was used to identify predictors of high (top quartile) and low (lowest quartile) serum aldosterone values. We estimated heritability of serum aldosterone via variance-component methods and evaluated linkage via a 10-cM-density genome scan. Results: Clinical variables related to higher serum aldosterone level included female sex, diuretic treatment, and a higher total/high density lipoprotein cholesterol ratio. A high urinary sodium excretion, postmenopausal status (without hormone replacement therapy), increased pulse pressure, and prevalent cardiovascular disease were related to lower serum aldosterone values. Urinary sodium was the strongest correlate of serum aldosterone (R2 = 10%). Serum aldosterone levels did not differ by genotype in the aldosterone synthase (CYP11B2c.1-344C>T) and the mineralocorticoid receptor (NR3C2c.754A>G) genes. The estimated heritability of serum aldosterone was 0.10. No chromosomal region attained a log-of-the-odds score >1 in multipoint linkage analysis. Conclusions: We observed a complex relation between serum aldosterone and vascular risk factors. The genetic contribution to serum aldosterone level was modest. [Copyright &y& Elsevier]
Published: 2005
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43. IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22?23.

Author: Gharavi, Ali G., Yan, Yan, Scolari, Francesco, Schena, F. Paolo, Frasca, Giovanni M., Ghiggeri, Gian Marco, Cooper, Kerry, Amoroso, Antonio, Viola, Battista Fabio, Battini, Graziana, Caridi, Gianluca, Canova, Cristina, Farhi, Anita, Subramanian, Vairavan, Nelson-Williams, Carol, Woodford, Sue, Julian, Bruce A., Wyatt, Robert J., and Lifton, Richard P.
Subjects: IGA glomerulonephritis, GLOMERULONEPHRITIS, GENETICS
Abstract: End-stage renal disease (ESRD) is a major public health problem, affecting 1 in 1,000 individuals and with an annual death rate of 20% despite dialysis treatment. IgA nephropathy (IgAN) is the most common form of glomerulonephritis, a principal cause of ESRD worldwide; it affects up to 1.3% of the population and its pathogenesis is unknown. Kidneys of people with IgAN show deposits of IgA-containing immune complexes with proliferation of the glomerular mesangium (Fig. 1). Typical clinical features include onset before age 40 with haematuria and proteinuria (blood and protein in the urine), and episodes of gross haematuria following mucosal infections are common; 30% of patients develop progressive renal failure. Although not generally considered a hereditary disease, striking ethnic variation in prevalence and familial clustering, along with subclinical renal abnormalities among relatives of IgAN cases, have suggested a heretofore undefined genetic component. By genome-wide analysis of linkage in 30 multiplex IgAN kindreds, we demonstrate linkage of IgAN to 6q22?23 under a dominant model of transmission with incomplete penetrance, with a lod score of 5.6 and 60% of kindreds linked. These findings for the first time indicate the existence of a locus with large effect on development of IgAN and identify the chromosomal location of this disease gene. [ABSTRACT FROM AUTHOR]
Published: 2000
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44. Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing.

Author: Smith, Annabel N., Skaug, Jennifer, Choate, Keith A., Nayir, Ahmet, Bakkaloglu, Aysin, Ozen, Seza, Hulton, Sally A., Sanjad, Sami A., Al-Sabban, Essam A., Lifton, Richard P., Scherer, Stephen W., and Karet, Fiona E.
Subjects: ACIDOSIS, KIDNEY diseases, GENETIC mutation, GENETICS
Abstract: The multi-subunit H+-ATPase pump is present at particularly high density on the apical (luminal) surface of α-intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification. The complete subunit composition of the apical ATPase, however, has not been fully agreed upon. Functional failure of α-intercalated cells results in a group of disorders, the distal renal tubular acidoses (dRTA), whose features include metabolic acidosis accompanied by disturbances of potassium balance, urinary calcium solubility, bone physiology and growth. Mutations in the gene encoding the B-subunit of the apical pump (ATP6B1) cause dRTA accompanied by deafness. We previously localized a gene for dRTA with preserved hearing to 7q33?34 (ref. 4). We report here the identification of this gene, ATP6N1B, which encodes an 840 amino acid novel kidney-specific isoform of ATP6N1A, the 116-kD non-catalytic accessory subunit of the proton pump. Northern-blot analysis demonstrated ATP6N1B expression in kidney but not other main organs. Immunofluorescence studies in human kidney cortex revealed that ATP6N1B localizes almost exclusively to the apical surface of α-intercalated cells. We screened nine dRTA kindreds with normal audiometry that linked to the ATP6N1B locus, and identified different homozygous mutations in ATP6N1B in eight. These include nonsense, deletion and splice-site changes, all of which will truncate the protein. Our findings identify a new kidney-specific proton pump 116-kD accessory subunit that is highly expressed in proton-secreting cells in the distal nephron, and illustrate its essential role in normal vectorial acid transport into the urine by the kidney. [ABSTRACT FROM AUTHOR]
Published: 2000
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45. IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype

Author: Perrault, Isabelle, Halbritter, Jan, Porath, Jonathan D, Gérard, Xavier, Braun, Daniela A, Gee, Heon Yung, Fathy, Hanan M, Saunier, Sophie, Cormier-Daire, Valérie, Thomas, Sophie, Attié-Bitach, Tania, Boddaert, Nathalie, Taschner, Michael, Schueler, Markus, Lorentzen, Esben, Lifton, Richard P, Lawson, Jennifer A, Garfa-Traore, Meriem, Otto, Edgar A, Bastin, Philippe, Caillaud, Catherine, Kaplan, Josseline, Rozet, Jean-Michel, and Hildebrandt, Friedhelm
Subjects: Genetics, Molecular genetics, Ophthalmology, Renal Medicine
Abstract: Background: Bidirectional intraflagellar transport (IFT) consists of two major protein complexes, IFT-A and IFT-B. In contrast to the IFT-B complex, all components of IFT-A have recently been linked to human ciliopathies when defective. We therefore hypothesised that mutations in additional IFT-B encoding genes can be found in patients with multisystemic ciliopathies. Methods: We screened 1628 individuals with reno-ocular ciliopathies by targeted next-generation sequencing of ciliary candidate genes, including all IFT-B encoding genes. Results: Consequently, we identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. Further, we detected a loss-of-stop mutation with extension of the deduced protein by 10 amino acids in an individual with neuronal ceroid lipofuscinosis-1. This proband presented with retinal dystrophy and brain lesions including cerebellar atrophy, a phenotype to which the IFT81 variant might contribute. Cultured fibroblasts of this latter affected individual showed a significant decrease in ciliated cell abundance compared with controls and increased expression of the transcription factor GLI2 suggesting deranged sonic hedgehog signalling. Conclusions: This work describes identification of mutations of IFT81 in individuals with symptoms consistent with the clinical spectrum of ciliopathies. It might represent the rare case of a core IFT-B complex protein found associated with human disease. Our data further suggest that defects in the IFT-B core are an exceedingly rare finding, probably due to its indispensable role for ciliary assembly in development.
Published: 2015
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46. The molecular basis of inherited hypokalemic alkalosis: Bartter's and Gitelman's syndromes.

Author: Simon, David B. and Lifton, Richard P.
Subjects: *KIDNEY diseases, *GENETICS
Abstract: Studies the molecular basis of inherited hypokalemic alkalosis Bartter's and Gitelman's syndromes. Possible mechanisms underlying the hypocalciuria and hypomagnesemia in affected patients; Proposed pathophysiology of Bartter's and Gitelman's syndromes; NKCC2 gene as the possible cause of Bartter's syndrome.
Published: 1996

47. Molecular genetics of human blood pressure variation.

Author: Lifton, Richard P.
Subjects: *BLOOD pressure, *VASCULAR diseases, *GENETICS
Abstract: Focuses on findings on the molecular genetics of human blood pressure diseases and variation. Mendelian forms of hypertension and hypotensions; Essential hypertension; Identification of genes in which mutations contribute to hypertension and hypotension.
Published: 1996
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48. A mutation causing pseudohypoaldosteronism type 1 identifies a conserved glycine that is involved in the gating of the epithelial sodium channel.

Author: Grunder, Stefan, Firsov, Dmitri, Chang, Sue S., Jaeger, Nicole Fowler, Gautschi, Ivan, Schild, Laurent, Lifton, Richard P., and Rossier, Bernard C.
Subjects: GENETIC mutation, HYPERALDOSTERONISM, ENDOCRINE diseases, SODIUM channels, ION channels, GLYCINE, AMINO acid neurotransmitters, GENETICS
Abstract: Pseudohypoaldosteronism type 1 (PHA-1) is an inherited disease characterized by severe neonatal salt-wasting and caused by mutations in subunits of the amiloride-sensitive epithelial sodium channel (ENaC). A missense mutation (G37S) of the human ENaC β subunit that causes loss of ENaC function and PHA-1 replaces a glycine that is conserved in the N-terminus of all members of the ENaC gene family. We now report an investigation of the mechanism of channel inactivation by this mutation. Homologous mutations, introduced into α, β or γ subunits, all significantly reduce macroscopic sodium channel currents recorded in Xenopus laevis oocytes. Quantitative determination of the number of channel molecules present at the cell surface showed no significant differences in surface expression of mutant compared with wild-type channels. Single channel conductances and ion selectivities of the mutant channels were identical to that of wild-type. These results suggest that the decrease in macroscopic Na currents is due to a decrease in channel open probability (Po), suggesting that mutations of a conserved glycine in the N-terminus of ENaC subunits change ENaC channel gating, which would explain the disease pathophysiology. Single channel recordings of channels containing the mutant α subunit (αG95S) directly demonstrate a striking reduction in Po. We propose that this mutation favors a gating mode characterized by short-open and long-closed times. We suggest that determination of the gating mode of ENaC is a key regulator of channel activity. [ABSTRACT FROM AUTHOR]
Published: 1997
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49. The Congenital Heart Disease Genetic Network Study: Cohort description

Author: Hoang, Thanh T., Goldmuntz, Elizabeth, Roberts, Amy E., Chung, Wendy K., Kline, Jennie K, Deanfield, John E., Giardini, Alessandro, Aleman, Adolfo, Gelb, Bruce D., Neal, Meghan Mac, Porter, George A., Kim, Richard, Brueckner, Martina, Lifton, Richard P., Edman, Sharon, Woyciechowski, Stacy, Mitchel, Laura E., and Agopian, A. J.
Subjects: Epidemiology, FOS: Biological sciences, Genetics, Pediatrics, 3. Good health, Congenital heart disease
Abstract: The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects) and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot) and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome). Cases with CHDs were recruited through ten sites, 2010–2014. Information on cases (N = 9,727) and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40%) or left ventricular outflow tract obstruction (21%). Across CHD types, there were significant differences (p

50. Individual Genomes on the Horizon.

Author: Lifton, Richard P.
Subjects: *MEDICAL research, *DIAGNOSIS, *NUCLEOTIDE sequence, *CLINICAL medicine, *GENETICS
Abstract: The author discusses the advances in genome sequencing that will play important roles in translating medical discoveries into clinical diagnosis. He says that the advances create numerous opportunities for the use of DNA sequencing in gene discovery. He also mentions that large reductions in costs can be accomplished by reducing the target for sequencing. He adds that DNA sequencing will be a major part of the diagnostic armamentarium routine.
Published: 2010
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