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364 results on '"Jhangiani, Shalini N."'

1. NODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy

Author: Dardas, Zain, Fatih, Jawid M., Jolly, Angad, Dawood, Moez, Du, Haowei, Grochowski, Christopher M., Jones, Edward G., Jhangiani, Shalini N., Wehrens, Xander H. T., Liu, Pengfei, Bi, Weimin, Boerwinkle, Eric, Posey, Jennifer E., Muzny, Donna M., Gibbs, Richard A., Lupski, James R., Coban-Akdemir, Zeynep, and Morris, Shaine A.
Published: 2024
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2. Phenotypic and mutational spectrum of ROR2‐related Robinow syndrome

Author: Lima, Ariadne R, Ferreira, Barbara M, Zhang, Chaofan, Jolly, Angad, Du, Haowei, White, Janson J, Dawood, Moez, Lins, Tulio C, Chiabai, Marcela A, Beusekom, Ellen, Cordoba, Mara S, Rosa, Erica CC Caldas, Kayserili, Hulya, Kimonis, Virginia, Wu, Erica, Mellado, Cecilia, Aggarwal, Vineet, Richieri‐Costa, Antonio, Brunoni, Décio, Canó, Talyta M, Jorge, Alexander AL, Kim, Chong A, Honjo, Rachel, Bertola, Débora R, Dandalo‐Girardi, Raissa M, Bayram, Yavuz, Gezdirici, Alper, Yilmaz‐Gulec, Elif, Gumus, Evren, Yilmaz, Gülay C, Okamoto, Nobuhiko, Ohashi, Hirofumi, Coban–Akdemir, Zeynep, Mitani, Tadahiro, Jhangiani, Shalini N, Muzny, Donna M, Regattieri, Neysa AP, Pogue, Robert, Pereira, Rinaldo W, Otto, Paulo A, Gibbs, Richard A, Ali, Bassam R, Bokhoven, Hans, Brunner, Han G, Sutton, V Reid, Lupski, James R, Vianna‐Morgante, Angela M, Carvalho, Claudia MB, and Mazzeu, Juliana F
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Pediatric, Congenital Structural Anomalies, Aetiology, 2.1 Biological and endogenous factors, Craniofacial Abnormalities, Dwarfism, Genes, Recessive, Humans, Limb Deformities, Congenital, Male, Phenotype, Receptor Tyrosine Kinase-like Orphan Receptors, Urogenital Abnormalities, chromosome microarray analysis, craniofacial morphology, exonic deletion, HPO terms, next-generation sequencing, quantitative phenotyping cluster heatmap, skeletal dysplasia, WNT pathway, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract: Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.
Published: 2022

3. Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci

Author: Grochowski, Christopher M., Bengtsson, Jesse D., Du, Haowei, Gandhi, Mira, Lun, Ming Yin, Mehaffey, Michele G., Park, KyungHee, Höps, Wolfram, Benito, Eva, Hasenfeld, Patrick, Korbel, Jan O., Mahmoud, Medhat, Paulin, Luis F., Jhangiani, Shalini N., Hwang, James Paul, Bhamidipati, Sravya V., Muzny, Donna M., Fatih, Jawid M., Gibbs, Richard A., Pendleton, Matthew, Harrington, Eoghan, Juul, Sissel, Lindstrand, Anna, Sedlazeck, Fritz J., Pehlivan, Davut, Lupski, James R., and Carvalho, Claudia M.B.
Published: 2024
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4. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum

Author: Calame, Daniel G., Wong, Jovi Huixin, Panda, Puravi, Nguyen, Dat Tuan, Leong, Nancy C.P., Sangermano, Riccardo, Patankar, Sohil G., Abdel-Hamid, Mohamed S., AlAbdi, Lama, Safwat, Sylvia, Flannery, Kyle P., Dardas, Zain, Fatih, Jawid M., Murali, Chaya, Kannan, Varun, Lotze, Timothy E., Herman, Isabella, Ammouri, Farah, Rezich, Brianna, Efthymiou, Stephanie, Alavi, Shahryar, Murphy, David, Firoozfar, Zahra, Nasab, Mahya Ebrahimi, Bahreini, Amir, Ghasemi, Majid, Haridy, Nourelhoda A., Goldouzi, Hamid Reza, Eghbal, Fatemeh, Karimiani, Ehsan Ghayoor, Begtrup, Amber, Elloumi, Houda, Srinivasan, Varunvenkat M., Gowda, Vykuntaraju K., Du, Haowei, Jhangiani, Shalini N., Coban-Akdemir, Zeynep, Marafi, Dana, Rodan, Lance, Isikay, Sedat, Rosenfeld, Jill A., Ramanathan, Subhadra, Staton, Michael, Oberg, Kerby C., Clark, Robin D., Wenman, Catharina, Loughlin, Sam, Saad, Ramy, Ashraf, Tazeen, Male, Alison, Tadros, Shereen, Boostani, Reza, Abdel-Salam, Ghada M.H., Zaki, Maha, Mardi, Ali, Hashemi-Gorji, Farzad, Abdalla, Ebtesam, Manzini, M. Chiara, Pehlivan, Davut, Posey, Jennifer E., Gibbs, Richard A., Houlden, Henry, Alkuraya, Fowzan S., Bujakowska, Kinga, Maroofian, Reza, Lupski, James R., and Nguyen, Long Nam
Published: 2024
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5. The impact of the Turkish population variome on the genomic architecture of rare disease traits

Author: Coban-Akdemir, Zeynep, Song, Xiaofei, Ceballos, Francisco C., Pehlivan, Davut, Karaca, Ender, Bayram, Yavuz, Mitani, Tadahiro, Gambin, Tomasz, Bozkurt-Yozgatli, Tugce, Jhangiani, Shalini N., Muzny, Donna M., Lewis, Richard A., Liu, Pengfei, Boerwinkle, Eric, Hamosh, Ada, Gibbs, Richard A., Sutton, V. Reid, Sobreira, Nara, Carvalho, Claudia M.B., Shaw, Chad A., Posey, Jennifer E., Valle, David, and Lupski, James R.
Published: 2024
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6. Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease

Author: Calame, Daniel G., Guo, Tianyu, Wang, Chen, Garrett, Lillian, Jolly, Angad, Dawood, Moez, Kurolap, Alina, Henig, Noa Zunz, Fatih, Jawid M., Herman, Isabella, Du, Haowei, Mitani, Tadahiro, Becker, Lore, Rathkolb, Birgit, Gerlini, Raffaele, Seisenberger, Claudia, Marschall, Susan, Hunter, Jill V., Gerard, Amanda, Heidlebaugh, Alexis, Challman, Thomas, Spillmann, Rebecca C., Jhangiani, Shalini N., Coban-Akdemir, Zeynep, Lalani, Seema, Liu, Lingxiao, Revah-Politi, Anya, Iglesias, Alejandro, Guzman, Edwin, Baugh, Evan, Boddaert, Nathalie, Rondeau, Sophie, Ormieres, Clothide, Barcia, Giulia, Tan, Queenie K.G., Thiffault, Isabelle, Pastinen, Tomi, Sheikh, Kazim, Biliciler, Suur, Mei, Davide, Melani, Federico, Shashi, Vandana, Yaron, Yuval, Steele, Mary, Wakeling, Emma, Østergaard, Elsebet, Nazaryan-Petersen, Lusine, Millan, Francisca, Santiago-Sim, Teresa, Thevenon, Julien, Bruel, Ange-Line, Thauvin-Robinet, Christel, Popp, Denny, Platzer, Konrad, Gawlinski, Pawel, Wiszniewski, Wojciech, Marafi, Dana, Pehlivan, Davut, Posey, Jennifer E., Gibbs, Richard A., Gailus-Durner, Valerie, Guerrini, Renzo, Fuchs, Helmut, Hrabě de Angelis, Martin, Hölter, Sabine M., Cheung, Hoi-Hung, Gu, Shen, and Lupski, James R.
Published: 2023
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7. Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome

Author: Jolly, Angad, Du, Haowei, Borel, Christelle, Chen, Na, Zhao, Sen, Grochowski, Christopher M., Duan, Ruizhi, Fatih, Jawid M., Dawood, Moez, Salvi, Sejal, Jhangiani, Shalini N., Muzny, Donna M., Koch, André, Rouskas, Konstantinos, Glentis, Stavros, Deligeoroglou, Efthymios, Bacopoulou, Flora, Wise, Carol A., Dietrich, Jennifer E., Van den Veyver, Ignatia B., Dimas, Antigone S., Brucker, Sara, Sutton, V. Reid, Gibbs, Richard A., Antonarakis, Stylianos E., Wu, Nan, Coban-Akdemir, Zeynep H., Zhu, Lan, Posey, Jennifer E., and Lupski, James R.
Published: 2023
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8. A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

Author: Ngo, Kathie J, Rexach, Jessica E, Lee, Hane, Petty, Lauren E, Perlman, Susan, Valera, Juliana M, Deignan, Joshua L, Mao, Yuanming, Aker, Mamdouh, Posey, Jennifer E, Jhangiani, Shalini N, Coban‐Akdemir, Zeynep H, Boerwinkle, Eric, Muzny, Donna, Nelson, Alexandra B, Hassin‐Baer, Sharon, Poke, Gemma, Neas, Katherine, Geschwind, Michael D, Grody, Wayne W, Gibbs, Richard, Geschwind, Daniel H, Lupski, James R, Below, Jennifer E, Nelson, Stanley F, and Fogel, Brent L
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Brain Disorders, Human Genome, Neurosciences, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Neurological, Cerebellar Ataxia, DNA Copy Number Variations, Exome, Genetic Association Studies, Genetic Linkage, Genetic Predisposition to Disease, Humans, Microsatellite Repeats, Nervous System Diseases, Exome Sequencing, ataxia, cerebellar ataxia, cerebellum, diagnostic testing, exome, gait disorders, genetics, genomics, neurogenetics, spastic paraparesis, spastic paraplegia, spinocerebellar ataxia, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract: Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.
Published: 2020

9. Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes

Author: Burrage, Lindsay C, Reynolds, John J, Baratang, Nissan Vida, Phillips, Jennifer B, Wegner, Jeremy, McFarquhar, Ashley, Higgs, Martin R, Christiansen, Audrey E, Lanza, Denise G, Seavitt, John R, Jain, Mahim, Li, Xiaohui, Parry, David A, Raman, Vandana, Chitayat, David, Chinn, Ivan K, Bertuch, Alison A, Karaviti, Lefkothea, Schlesinger, Alan E, Earl, Dawn, Bamshad, Michael, Savarirayan, Ravi, Doddapaneni, Harsha, Muzny, Donna, Jhangiani, Shalini N, Eng, Christine M, Gibbs, Richard A, Bi, Weimin, Emrick, Lisa, Rosenfeld, Jill A, Postlethwait, John, Westerfield, Monte, Dickinson, Mary E, Beaudet, Arthur L, Ranza, Emmanuelle, Huber, Celine, Cormier-Daire, Valérie, Shen, Wei, Mao, Rong, Heaney, Jason D, Orange, Jordan S, Genomics, University of Washington Center for Mendelian, Network, Undiagnosed Diseases, Adams, David R, Aday, Aaron, Alejandro, Mercedes E, Allard, Patrick, Ashley, Euan A, Azamian, Mahshid S, Bacino, Carlos A, Baker, Eva, Balasubramanyam, Ashok, Barseghyan, Hayk, Batzli, Gabriel F, Beggs, Alan H, Behnam, Babak, Bellen, Hugo J, Bernstein, Jonathan A, Berry, Gerard T, Bican, Anna, Bick, David P, Birch, Camille L, Bonner, Devon, Boone, Braden E, Bostwick, Bret L, Briere, Lauren C, Brokamp, Elly, Brown, Donna M, Brush, Matthew, Burke, Elizabeth A, Butte, Manish J, Chen, Shan, Clark, Gary D, Coakley, Terra R, Cogan, Joy D, Colley, Heather A, Cooper, Cynthia M, Cope, Heidi, Craigen, William J, D’Souza, Precilla, Davids, Mariska, Davidson, Jean M, Dayal, Jyoti G, Dell’Angelica, Esteban C, Dhar, Shweta U, Dipple, Katrina M, Donnell-Fink, Laurel A, Dorrani, Naghmeh, Dorset, Daniel C, Douine, Emilie D, Draper, David D, Dries, Annika M, Duncan, Laura, Eckstein, David J, Emrick, Lisa T, Enns, Gregory M, Eskin, Ascia, and Esteves, Cecilia
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Clinical Research, Congenital Structural Anomalies, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Alleles, Animals, Cells, Cultured, Child, Child, Preschool, Chromosomal Instability, DNA Damage, Female, Fibroblasts, Genetic Association Studies, Genetic Variation, Humans, Mice, Mice, Knockout, Musculoskeletal Abnormalities, NF-kappa B, Osteochondrodysplasias, Exome Sequencing, Young Adult, Zebrafish, University of Washington Center for Mendelian Genomics, Undiagnosed Diseases Network, DNA repair, DNA replication, SPONASTRIME dysplasia, TONSL, exome sequencing, skeletal dysplasia, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract: SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.
Published: 2019

10. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Author: Cogné, Benjamin, Ehresmann, Sophie, Beauregard-Lacroix, Eliane, Rousseau, Justine, Besnard, Thomas, Garcia, Thomas, Petrovski, Slavé, Avni, Shiri, McWalter, Kirsty, Blackburn, Patrick R, Sanders, Stephan J, Uguen, Kévin, Harris, Jacqueline, Cohen, Julie S, Blyth, Moira, Lehman, Anna, Berg, Jonathan, Li, Mindy H, Kini, Usha, Joss, Shelagh, von der Lippe, Charlotte, Gordon, Christopher T, Humberson, Jennifer B, Robak, Laurie, Scott, Daryl A, Sutton, Vernon R, Skraban, Cara M, Johnston, Jennifer J, Poduri, Annapurna, Nordenskjöld, Magnus, Shashi, Vandana, Gerkes, Erica H, Bongers, Ernie MHF, Gilissen, Christian, Zarate, Yuri A, Kvarnung, Malin, Lally, Kevin P, Kulch, Peggy A, Daniels, Brina, Hernandez-Garcia, Andres, Stong, Nicholas, McGaughran, Julie, Retterer, Kyle, Tveten, Kristian, Sullivan, Jennifer, Geisheker, Madeleine R, Stray-Pedersen, Asbjorg, Tarpinian, Jennifer M, Klee, Eric W, Sapp, Julie C, Zyskind, Jacob, Holla, Øystein L, Bedoukian, Emma, Filippini, Francesca, Guimier, Anne, Picard, Arnaud, Busk, Øyvind L, Punetha, Jaya, Pfundt, Rolph, Lindstrand, Anna, Nordgren, Ann, Kalb, Fayth, Desai, Megha, Ebanks, Ashley Harmon, Jhangiani, Shalini N, Dewan, Tammie, Coban Akdemir, Zeynep H, Telegrafi, Aida, Zackai, Elaine H, Begtrup, Amber, Song, Xiaofei, Toutain, Annick, Wentzensen, Ingrid M, Odent, Sylvie, Bonneau, Dominique, Latypova, Xénia, Deb, Wallid, CAUSES Study, Redon, Sylvia, Bilan, Frédéric, Legendre, Marine, Troyer, Caitlin, Whitlock, Kerri, Caluseriu, Oana, Murphree, Marine I, Pichurin, Pavel N, Agre, Katherine, Gavrilova, Ralitza, Rinne, Tuula, Park, Meredith, Shain, Catherine, Heinzen, Erin L, Xiao, Rui, Amiel, Jeanne, Lyonnet, Stanislas, Isidor, Bertrand, Biesecker, Leslie G, Lowenstein, Dan, Posey, Jennifer E, and Denommé-Pichon, Anne-Sophie
Subjects: CAUSES Study, Deciphering Developmental Disorders study, Humans, Syndrome, Adaptor Proteins, Signal Transducing, Nuclear Proteins, Prognosis, Autistic Disorder, Amino Acid Sequence, Sequence Homology, Mutation, Missense, Adolescent, Adult, Child, Child, Preschool, Infant, Female, Male, Young Adult, Genetic Association Studies, Intellectual Disability, TRRAP, autism spectrum disorder, congenital malformations, de novo variants, histone acetylation, intellectual disability, neurodevelopmental disorders, Intellectual and Developmental Disabilities (IDD), Pediatric, Genetics, Brain Disorders, Neurosciences, Mental Health, Autism, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Mental health, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
Published: 2019

11. The multiple de novo copy number variant (MdnCNV) phenomenon presents with peri-zygotic DNA mutational signatures and multilocus pathogenic variation

Author: Du, Haowei, Jolly, Angad, Grochowski, Christopher M., Yuan, Bo, Dawood, Moez, Jhangiani, Shalini N., Li, He, Muzny, Donna, Fatih, Jawid M., Coban-Akdemir, Zeynep, Carlin, Mary Esther, Scheuerle, Angela E., Witzl, Karin, Posey, Jennifer E., Pendleton, Matthew, Harrington, Eoghan, Juul, Sissel, Hastings, P. J., Bi, Weimin, Gibbs, Richard A., Sedlazeck, Fritz J., Lupski, James R., Carvalho, Claudia M. B., and Liu, Pengfei
Published: 2022
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12. Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy

Author: Calame, Daniel G., Bakhtiari, Somayeh, Logan, Rachel, Coban-Akdemir, Zeynep, Du, Haowei, Mitani, Tadahiro, Fatih, Jawid M., Hunter, Jill V., Herman, Isabella, Pehlivan, Davut, Jhangiani, Shalini N., Person, Richard, Schnur, Rhonda E., Jin, Sheng Chih, Bilguvar, Kaya, Posey, Jennifer E., Koh, Sookyong, Firouzabadi, Saghar G., Alehabib, Elham, Tafakhori, Abbas, Esmkhani, Sahra, Gibbs, Richard A., Noureldeen, Mahmoud M., Zaki, Maha S., Marafi, Dana, Darvish, Hossein, Kruer, Michael C., and Lupski, James R.
Published: 2021
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13. IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease

Author: Cananzi, Mara, Wohler, Elizabeth, Marzollo, Antonio, Colavito, Davide, You, Jing, Jing, Huie, Bresolin, Silvia, Gaio, Paola, Martin, Renan, Mescoli, Claudia, Bade, Sangeeta, Posey, Jennifer E., Dalle Carbonare, Maurizio, Tung, Wesley, Jhangiani, Shalini N., Bosa, Luca, Zhang, Yu, Filho, Joselito Sobreira, Gabelli, Maria, Kellermayer, Richard, Kader, Howard A., Oliva-Hemker, Maria, Perilongo, Giorgio, Lupski, James R., Biffi, Alessandra, Valle, David, Leon, Alberta, de Macena Sobreira, Nara Lygia, Su, Helen C., and Guerrerio, Anthony L.
Published: 2021
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14. Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies

Author: Dworschak, Gabriel C., Punetha, Jaya, Kalanithy, Jeshurun C., Mingardo, Enrico, Erdem, Haktan B., Akdemir, Zeynep C., Karaca, Ender, Mitani, Tadahiro, Marafi, Dana, Fatih, Jawid M., Jhangiani, Shalini N., Hunter, Jill V., Dakal, Tikam Chand, Dhabhai, Bhanupriya, Dabbagh, Omar, Alsaif, Hessa S., Alkuraya, Fowzan S., Maroofian, Reza, Houlden, Henry, Efthymiou, Stephanie, Dominik, Natalia, Salpietro, Vincenzo, Sultan, Tipu, Haider, Shahzad, Bibi, Farah, Thiele, Holger, Hoefele, Julia, Riedhammer, Korbinian M., Wagner, Matias, Guella, Ilaria, Demos, Michelle, Keren, Boris, Buratti, Julien, Charles, Perrine, Nava, Caroline, Héron, Delphine, Heide, Solveig, Valkanas, Elise, Waddell, Leigh B., Jones, Kristi J., Oates, Emily C., Cooper, Sandra T., MacArthur, Daniel, Syrbe, Steffen, Ziegler, Andreas, Platzer, Konrad, Okur, Volkan, Chung, Wendy K., O’Shea, Sarah A., Alcalay, Roy, Fahn, Stanley, Mark, Paul R., Guerrini, Renzo, Vetro, Annalisa, Hudson, Beth, Schnur, Rhonda E., Hoganson, George E., Burton, Jennifer E., McEntagart, Meriel, Lindenberg, Tobias, Yilmaz, Öznur, Odermatt, Benjamin, Pehlivan, Davut, Posey, Jennifer E., Lupski, James R., and Reutter, Heiko
Published: 2021
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15. Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Author: Stray-Pedersen, Asbjørg, Sorte, Hanne Sørmo, Samarakoon, Pubudu, Gambin, Tomasz, Chinn, Ivan K, Akdemir, Zeynep H Coban, Erichsen, Hans Christian, Forbes, Lisa R, Gu, Shen, Yuan, Bo, Jhangiani, Shalini N, Muzny, Donna M, Rødningen, Olaug Kristin, Sheng, Ying, Nicholas, Sarah K, Noroski, Lenora M, Seeborg, Filiz O, Davis, Carla M, Canter, Debra L, Mace, Emily M, Vece, Timothy J, Allen, Carl E, Abhyankar, Harshal A, Boone, Philip M, Beck, Christine R, Wiszniewski, Wojciech, Fevang, Børre, Aukrust, Pål, Tjønnfjord, Geir E, Gedde-Dahl, Tobias, Hjorth-Hansen, Henrik, Dybedal, Ingunn, Nordøy, Ingvild, Jørgensen, Silje F, Abrahamsen, Tore G, Øverland, Torstein, Bechensteen, Anne Grete, Skogen, Vegard, Osnes, Liv TN, Kulseth, Mari Ann, Prescott, Trine E, Rustad, Cecilie F, Heimdal, Ketil R, Belmont, John W, Rider, Nicholas L, Chinen, Javier, Cao, Tram N, Smith, Eric A, Caldirola, Maria Soledad, Bezrodnik, Liliana, Reyes, Saul Oswaldo Lugo, Rosales, Francisco J Espinosa, Guerrero-Cursaru, Nina Denisse, Pedroza, Luis Alberto, Poli, Cecilia M, Franco, Jose L, Vargas, Claudia M Trujillo, Becerra, Juan Carlos Aldave, Wright, Nicola, Issekutz, Thomas B, Issekutz, Andrew C, Abbott, Jordan, Caldwell, Jason W, Bayer, Diana K, Chan, Alice Y, Aiuti, Alessandro, Cancrini, Caterina, Holmberg, Eva, West, Christina, Burstedt, Magnus, Karaca, Ender, Yesil, Gözde, Artac, Hasibe, Bayram, Yavuz, Atik, Mehmed Musa, Eldomery, Mohammad K, Ehlayel, Mohammad S, Jolles, Stephen, Flatø, Berit, Bertuch, Alison A, Hanson, I Celine, Zhang, Victor W, Wong, Lee-Jun, Hu, Jianhong, Walkiewicz, Magdalena, Yang, Yaping, Eng, Christine M, Boerwinkle, Eric, Gibbs, Richard A, Shearer, William T, Lyle, Robert, Orange, Jordan S, and Lupski, James R
Subjects: Biomedical and Clinical Sciences, Immunology, Human Genome, Prevention, Clinical Research, Genetic Testing, Genetics, Rare Diseases, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Good Health and Well Being, Adolescent, Adult, Aged, Child, Child, Preschool, DNA Copy Number Variations, Female, Genomics, High-Throughput Nucleotide Sequencing, Humans, Immunologic Deficiency Syndromes, Infant, Male, Middle Aged, Young Adult, Primary immunodeficiency disease, whole-exome sequencing, copy number variants, Allergy
Abstract: BackgroundPrimary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.ObjectiveWe sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.MethodsPatients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping.ResultsA likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays.ConclusionThis high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
Published: 2017

16. Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2

Author: Sajan, Samin A, Jhangiani, Shalini N, Muzny, Donna M, Gibbs, Richard A, Lupski, James R, Glaze, Daniel G, Kaufmann, Walter E, Skinner, Steven A, Annese, Fran, Friez, Michael J, Lane, Jane, Percy, Alan K, and Neul, Jeffrey L
Subjects: Biological Sciences, Genetics, Mental Health, Pediatric, Rett Syndrome, Rare Diseases, Neurodegenerative, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Neurosciences, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Congenital, Adolescent, Adult, Child, Child, Preschool, Chromatin, DNA Copy Number Variations, Female, Forkhead Transcription Factors, Humans, Infant, Male, Methyl-CpG-Binding Protein 2, Mutation, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases, Exome Sequencing, chromatin regulation, CNV, exome sequencing, glutamate signaling, Rett syndrome, Clinical Sciences, Genetics & Heredity
Abstract: PurposeRett syndrome (RTT) is a neurodevelopmental disorder caused primarily by de novo mutations in MECP2 and sometimes in CDKL5 and FOXG1. However, some RTT patients lack mutations in these genes.MethodsTwenty-two RTT patients without apparent MECP2, CDKL5, and FOXG1 mutations were subjected to both whole-exome sequencing and single-nucleotide polymorphism array-based copy-number variant (CNV) analyses.ResultsThree patients had MECP2 mutations initially missed by clinical testing. Of the remaining 19, 17 (89.5%) had 29 other likely pathogenic intragenic mutations and/or CNVs (10 patients had 2 or more). Interestingly, 13 patients had mutations in a gene/region previously reported in other neurodevelopmental disorders (NDDs), thereby providing a potential diagnostic yield of 68.4%. These mutations were significantly enriched in chromatin regulators (corrected P = 0.0068) and moderately enriched in postsynaptic cell membrane molecules (corrected P = 0.076), implicating glutamate receptor signaling.ConclusionThe genetic etiology of RTT without MECP2, CDKL5, and FOXG1 mutations is heterogeneous, overlaps with other NDDs, and complicated by a high mutation burden. Dysregulation of chromatin structure and abnormal excitatory synaptic signaling may form two common pathological bases of RTT.Genet Med 19 1, 13-19.
Published: 2017

17. Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland

Author: Järvelä, Irma, Määttä, Tuomo, Acharya, Anushree, Leppälä, Juha, Jhangiani, Shalini N., Arvio, Maria, Siren, Auli, Kankuri-Tammilehto, Minna, Kokkonen, Hannaleena, Palomäki, Maarit, Varilo, Teppo, Fang, Mary, Hadley, Trevor D., Jolly, Angad, Linnankivi, Tarja, Paetau, Ritva, Saarela, Anni, Kälviäinen, Reetta, Olme, Jan, Nouel-Saied, Liz M., Cornejo-Sanchez, Diana M., Llaci, Lorida, Lupski, James R., Posey, Jennifer E., Leal, Suzanne M., and Schrauwen, Isabelle
Published: 2021
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18. High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population

Author: Mitani, Tadahiro, Isikay, Sedat, Gezdirici, Alper, Gulec, Elif Yilmaz, Punetha, Jaya, Fatih, Jawid M., Herman, Isabella, Akay, Gulsen, Du, Haowei, Calame, Daniel G., Ayaz, Akif, Tos, Tulay, Yesil, Gozde, Aydin, Hatip, Geckinli, Bilgen, Elcioglu, Nursel, Candan, Sukru, Sezer, Ozlem, Erdem, Haktan Bagis, Gul, Davut, Demiral, Emine, Elmas, Muhsin, Yesilbas, Osman, Kilic, Betul, Gungor, Serdal, Ceylan, Ahmet C., Bozdogan, Sevcan, Ozalp, Ozge, Cicek, Salih, Aslan, Huseyin, Yalcintepe, Sinem, Topcu, Vehap, Bayram, Yavuz, Grochowski, Christopher M., Jolly, Angad, Dawood, Moez, Duan, Ruizhi, Jhangiani, Shalini N., Doddapaneni, Harsha, Hu, Jianhong, Muzny, Donna M., Marafi, Dana, Akdemir, Zeynep Coban, Karaca, Ender, Carvalho, Claudia M.B., Gibbs, Richard A., Posey, Jennifer E., Lupski, James R., and Pehlivan, Davut
Published: 2021
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19. DVL3 Alleles Resulting in a −1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome

Author: White, Janson J, Mazzeu, Juliana F, Hoischen, Alexander, Bayram, Yavuz, Withers, Marjorie, Gezdirici, Alper, Kimonis, Virginia, Steehouwer, Marloes, Jhangiani, Shalini N, Muzny, Donna M, Gibbs, Richard A, Genomics, Baylor-Hopkins Center for Mendelian, van Bon, Bregje WM, Sutton, V Reid, Lupski, James R, Brunner, Han G, and Carvalho, Claudia MB
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Congenital Structural Anomalies, Clinical Research, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Congenital, Adaptor Proteins, Signal Transducing, Alleles, Base Sequence, Codon, Nonsense, Craniofacial Abnormalities, Dishevelled Proteins, Dwarfism, Exons, Female, Frameshift Mutation, Genetic Variation, Humans, Limb Deformities, Congenital, Male, Molecular Sequence Data, Phosphoproteins, Proto-Oncogene Proteins, Receptor Tyrosine Kinase-like Orphan Receptors, Sequence Analysis, DNA, Sequence Deletion, Urogenital Abnormalities, Wnt Proteins, Wnt-5a Protein, Baylor-Hopkins Center for Mendelian Genomics, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract: Robinow syndrome is a rare congenital disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features. Recent reports have identified, in individuals with dominant Robinow syndrome, a specific type of variant characterized by being uniformly located in the penultimate exon of DVL1 and resulting in a -1 frameshift allele with a premature termination codon that escapes nonsense-mediated decay. Here, we studied a cohort of individuals who had been clinically diagnosed with Robinow syndrome but who had not received a molecular diagnosis from variant studies of DVL1, WNT5A, and ROR2. Because of the uniform location of frameshift variants in DVL1-mediated Robinow syndrome and the functional redundancy of DVL1, DVL2, and DVL3, we elected to pursue direct Sanger sequencing of the penultimate exon of DVL1 and its paralogs DVL2 and DVL3 to search for potential disease-associated variants. Remarkably, targeted sequencing identified five unrelated individuals harboring heterozygous, de novo frameshift variants in DVL3, including two splice acceptor mutations and three 1 bp deletions. Similar to the variants observed in DVL1-mediated Robinow syndrome, all variants in DVL3 result in a -1 frameshift, indicating that these highly specific alterations might be a common cause of dominant Robinow syndrome. Here, we review the current knowledge of these peculiar variant alleles in DVL1- and DVL3-mediated Robinow syndrome and further elucidate the phenotypic features present in subjects with DVL1 and DVL3 frameshift mutations.
Published: 2016

20. DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome.

Author: White, Janson J, Mazzeu, Juliana F, Hoischen, Alexander, Bayram, Yavuz, Withers, Marjorie, Gezdirici, Alper, Kimonis, Virginia, Steehouwer, Marloes, Jhangiani, Shalini N, Muzny, Donna M, Gibbs, Richard A, Baylor-Hopkins Center for Mendelian Genomics, van Bon, Bregje WM, Sutton, V Reid, Lupski, James R, Brunner, Han G, and Carvalho, Claudia MB
Subjects: Baylor-Hopkins Center for Mendelian Genomics, Humans, Dwarfism, Craniofacial Abnormalities, Limb Deformities, Congenital, Urogenital Abnormalities, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins, Phosphoproteins, Codon, Nonsense, Sequence Analysis, DNA, Sequence Deletion, Base Sequence, Frameshift Mutation, Alleles, Exons, Molecular Sequence Data, Female, Male, Wnt Proteins, Genetic Variation, Receptor Tyrosine Kinase-like Orphan Receptors, Wnt-5a Protein, Dishevelled Proteins, Rare Diseases, Congenital Structural Anomalies, Clinical Research, Pediatric, Genetics, 2.1 Biological and endogenous factors, Aetiology, Congenital, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Robinow syndrome is a rare congenital disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features. Recent reports have identified, in individuals with dominant Robinow syndrome, a specific type of variant characterized by being uniformly located in the penultimate exon of DVL1 and resulting in a -1 frameshift allele with a premature termination codon that escapes nonsense-mediated decay. Here, we studied a cohort of individuals who had been clinically diagnosed with Robinow syndrome but who had not received a molecular diagnosis from variant studies of DVL1, WNT5A, and ROR2. Because of the uniform location of frameshift variants in DVL1-mediated Robinow syndrome and the functional redundancy of DVL1, DVL2, and DVL3, we elected to pursue direct Sanger sequencing of the penultimate exon of DVL1 and its paralogs DVL2 and DVL3 to search for potential disease-associated variants. Remarkably, targeted sequencing identified five unrelated individuals harboring heterozygous, de novo frameshift variants in DVL3, including two splice acceptor mutations and three 1 bp deletions. Similar to the variants observed in DVL1-mediated Robinow syndrome, all variants in DVL3 result in a -1 frameshift, indicating that these highly specific alterations might be a common cause of dominant Robinow syndrome. Here, we review the current knowledge of these peculiar variant alleles in DVL1- and DVL3-mediated Robinow syndrome and further elucidate the phenotypic features present in subjects with DVL1 and DVL3 frameshift mutations.
Published: 2016

21. PhenoDB, GeneMatcher and VariantMatcher, tools for analysis and sharing of sequence data

Author: Wohler, Elizabeth, Martin, Renan, Griffith, Sean, Rodrigues, Eliete da S., Antonescu, Corina, Posey, Jennifer E., Coban-Akdemir, Zeynep, Jhangiani, Shalini N., Doheny, Kimberly F., Lupski, James R., Valle, David, Hamosh, Ada, and Sobreira, Nara
Published: 2021
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22. Human NK cell deficiency as a result of biallelic mutations in MCM10

Author: Mace, Emily M., Paust, Silke, Conte, Matilde I., Baxley, Ryan M., Schmit, Megan M., Patil, Sagar L., Guilz, Nicole C., Mukherjee, Malini, Pezzi, Ashley E., Chmielowiec, Jolanta, Tatineni, Swetha, Chinn, Ivan K., Akdemir, Zeynep Coban, Jhangiani, Shalini N., Muzny, Donna M., Stray-Pedersen, Asbjorg, Bradley, Rachel E., Moody, Mo, Connor, Philip P., Heaps, Adrian G., Steward, Colin, Banerjee, Pinaki P., Gibbs, Richard A., Borowiak, Malgorzata, Lupski, James R., Jolles, Stephen, Bielinsky, Anja K., and Orange, Jordan S.
Subjects: United States. National Center for Advancing Translational Sciences -- Analysis, Killer cells -- Genetic aspects -- Analysis, Disease susceptibility -- Genetic aspects, Stem cells -- Genetic aspects -- Analysis, Health care industry, Texas Children's Hospital
Abstract: Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage-response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function., Introduction Human natural killer (NK) cells play a critical role in the control of viral infection and malignancy through contact-mediated killing of susceptible target cells and cytokine secretion. While rare, [...]
Published: 2020
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23. Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID

Author: Kuhny, Marcel, Forbes, Lisa R., Cakan, Elif, Vega-Loza, Andrea, Kostiuk, Valentyna, Dinesh, Ravi K., Glauzy, Salome, Stray-Pedersen, Asbjorg, Pezzi, Ashley E., Hanson, I. Celine, Vargas-Hernandez, Alexander, Xu, Mina LuQuing, Coban-Akdemir, Zeynep H., Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Lupski, James R., Chinn, Ivan K., Schatz, David G., Orange, Jordan S., and Meffre, Eric
Subjects: Thermo Fisher Scientific Inc. -- International economic relations, B cells -- Genetic aspects, Immunoglobulin G, Health care industry
Abstract: Patients with common variable immunodeficiency associated with autoimmune cytopenia (CVID+AIC) generate few isotypeswitched B cells with severely decreased frequencies of somatic hypermutations (SHMs), but their underlying molecular defects remain poorly characterized. We identified a CVID+AIC patient who displays a rare homozygous missense M466V mutation in [beta]-catenin-like protein 1 (CTNNBL1). Because CTNNBL1 binds activation-induced cytidine deaminase (AID) that catalyzes SHM, we tested AID interactions with the CTNNBL1 M466V variant. We found that the M466V mutation interfered with the association of CTNNBL1 with AID, resulting in decreased AID in the nuclei of patient EBV-transformed B cell lines and of CTNNBL1 [466.sup.V/V] Ramos B cells engineered to express only CTNNBL1 M466V using CRISPR/Cas9 technology. As a consequence, the scarce IgG+ memory B cells from the CTNNBL1 [466.sup.V/V] patient showed a low SHM frequency that averaged 6.7 mutations compared with about 18 mutations per clone in healthy-donor counterparts. In addition, CTNNBL1 [466.sup.V/V] Ramos B cells displayed a decreased incidence of SHM that was reduced by half compared with parental WT Ramos B cells, demonstrating that the CTNNBL1 M466V mutation is responsible for defective SHM induction. We conclude that CTNNBL1 plays an important role in regulating AID-dependent antibody diversification in humans., Introduction Isotype-switched high-affinity antibodies are essential for protection against a vast range of pathogens. Activation-induced cytidine deaminase (AID) is the enzyme that mediates somatic hypermutation (SHM) and class-switch recombination (CSR), [...]
Published: 2020
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24. Low-level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected Mendelian conditions

Author: Gambin, Tomasz, Liu, Qian, Karolak, Justyna A., Grochowski, Christopher M., Xie, Nina G., Wu, Lucia R., Yan, Yan Helen, Cao, Ye, Coban Akdemir, Zeynep H., Wilson, Theresa A., Jhangiani, Shalini N., Chen, Ed, Eng, Christine M., Muzny, Donna, Posey, Jennifer E., Yang, Yaping, Zhang, David Y., Shaw, Chad, Liu, Pengfei, Lupski, James R., and Stankiewicz, Paweł
Published: 2020
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25. Hemichordate genomes and deuterostome origins.

Author: Simakov, Oleg, Kawashima, Takeshi, Marlétaz, Ferdinand, Jenkins, Jerry, Koyanagi, Ryo, Mitros, Therese, Hisata, Kanako, Bredeson, Jessen, Shoguchi, Eiichi, Gyoja, Fuki, Yue, Jia-Xing, Chen, Yi-Chih, Freeman, Robert M, Sasaki, Akane, Hikosaka-Katayama, Tomoe, Sato, Atsuko, Fujie, Manabu, Baughman, Kenneth W, Levine, Judith, Gonzalez, Paul, Cameron, Christopher, Fritzenwanker, Jens H, Pani, Ariel M, Goto, Hiroki, Kanda, Miyuki, Arakaki, Nana, Yamasaki, Shinichi, Qu, Jiaxin, Cree, Andrew, Ding, Yan, Dinh, Huyen H, Dugan, Shannon, Holder, Michael, Jhangiani, Shalini N, Kovar, Christie L, Lee, Sandra L, Lewis, Lora R, Morton, Donna, Nazareth, Lynne V, Okwuonu, Geoffrey, Santibanez, Jireh, Chen, Rui, Richards, Stephen, Muzny, Donna M, Gillis, Andrew, Peshkin, Leonid, Wu, Michael, Humphreys, Tom, Su, Yi-Hsien, Putnam, Nicholas H, Schmutz, Jeremy, Fujiyama, Asao, Yu, Jr-Kai, Tagawa, Kunifumi, Worley, Kim C, Gibbs, Richard A, Kirschner, Marc W, Lowe, Christopher J, Satoh, Noriyuki, Rokhsar, Daniel S, and Gerhart, John
Subjects: Animals, Chordata, Nonvertebrate, Echinodermata, Transforming Growth Factor beta, Evolution, Molecular, Phylogeny, Signal Transduction, Conserved Sequence, Synteny, Multigene Family, Genome, Chordata, Nonvertebrate, Evolution, Molecular, General Science & Technology
Abstract: Acorn worms, also known as enteropneust (literally, 'gut-breathing') hemichordates, are marine invertebrates that share features with echinoderms and chordates. Together, these three phyla comprise the deuterostomes. Here we report the draft genome sequences of two acorn worms, Saccoglossus kowalevskii and Ptychodera flava. By comparing them with diverse bilaterian genomes, we identify shared traits that were probably inherited from the last common deuterostome ancestor, and then explore evolutionary trajectories leading from this ancestor to hemichordates, echinoderms and chordates. The hemichordate genomes exhibit extensive conserved synteny with amphioxus and other bilaterians, and deeply conserved non-coding sequences that are candidates for conserved gene-regulatory elements. Notably, hemichordates possess a deuterostome-specific genomic cluster of four ordered transcription factor genes, the expression of which is associated with the development of pharyngeal 'gill' slits, the foremost morphological innovation of early deuterostomes, and is probably central to their filter-feeding lifestyle. Comparative analysis reveals numerous deuterostome-specific gene novelties, including genes found in deuterostomes and marine microbes, but not other animals. The putative functions of these genes can be linked to physiological, metabolic and developmental specializations of the filter-feeding ancestor.
Published: 2015

26. COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis

Author: Watkin, Levi B, Jessen, Birthe, Wiszniewski, Wojciech, Vece, Timothy J, Jan, Max, Sha, Youbao, Thamsen, Maike, Santos-Cortez, Regie LP, Lee, Kwanghyuk, Gambin, Tomasz, Forbes, Lisa R, Law, Christopher S, Stray-Pedersen, Asbjørg, Cheng, Mickie H, Mace, Emily M, Anderson, Mark S, Liu, Dongfang, Tang, Ling Fung, Nicholas, Sarah K, Nahmod, Karen, Makedonas, George, Canter, Debra L, Kwok, Pui-Yan, Hicks, John, Jones, Kirk D, Penney, Samantha, Jhangiani, Shalini N, Rosenblum, Michael D, Dell, Sharon D, Waterfield, Michael R, Papa, Feroz R, Muzny, Donna M, Zaitlen, Noah, Leal, Suzanne M, Gonzaga-Jauregui, Claudia, Boerwinkle, Eric, Eissa, N Tony, Gibbs, Richard A, Lupski, James R, Orange, Jordan S, and Shum, Anthony K
Subjects: Biochemistry and Cell Biology, Biological Sciences, Autoimmune Disease, Lung, Arthritis, Genetics, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Amino Acid Sequence, Autoimmune Diseases, Child, Preschool, Coatomer Protein, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Female, Genetic Association Studies, Genetic Predisposition to Disease, Golgi Apparatus, HEK293 Cells, Humans, Infant, Lod Score, Lung Diseases, Interstitial, Male, Molecular Sequence Data, Pedigree, Protein Transport, Baylor-Hopkins Center for Mendelian Genomics, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.
Published: 2015

27. The First Myriapod Genome Sequence Reveals Conservative Arthropod Gene Content and Genome Organisation in the Centipede Strigamia maritima

Author: Chipman, Ariel D, Ferrier, David EK, Brena, Carlo, Qu, Jiaxin, Hughes, Daniel ST, Schröder, Reinhard, Torres-Oliva, Montserrat, Znassi, Nadia, Jiang, Huaiyang, Almeida, Francisca C, Alonso, Claudio R, Apostolou, Zivkos, Aqrawi, Peshtewani, Arthur, Wallace, Barna, Jennifer CJ, Blankenburg, Kerstin P, Brites, Daniela, Capella-Gutiérrez, Salvador, Coyle, Marcus, Dearden, Peter K, Du Pasquier, Louis, Duncan, Elizabeth J, Ebert, Dieter, Eibner, Cornelius, Erikson, Galina, Evans, Peter D, Extavour, Cassandra G, Francisco, Liezl, Gabaldón, Toni, Gillis, William J, Goodwin-Horn, Elizabeth A, Green, Jack E, Griffiths-Jones, Sam, Grimmelikhuijzen, Cornelis JP, Gubbala, Sai, Guigó, Roderic, Han, Yi, Hauser, Frank, Havlak, Paul, Hayden, Luke, Helbing, Sophie, Holder, Michael, Hui, Jerome HL, Hunn, Julia P, Hunnekuhl, Vera S, Jackson, LaRonda, Javaid, Mehwish, Jhangiani, Shalini N, Jiggins, Francis M, Jones, Tamsin E, Kaiser, Tobias S, Kalra, Divya, Kenny, Nathan J, Korchina, Viktoriya, Kovar, Christie L, Kraus, F Bernhard, Lapraz, François, Lee, Sandra L, Lv, Jie, Mandapat, Christigale, Manning, Gerard, Mariotti, Marco, Mata, Robert, Mathew, Tittu, Neumann, Tobias, Newsham, Irene, Ngo, Dinh N, Ninova, Maria, Okwuonu, Geoffrey, Ongeri, Fiona, Palmer, William J, Patil, Shobha, Patraquim, Pedro, Pham, Christopher, Pu, Ling-Ling, Putman, Nicholas H, Rabouille, Catherine, Ramos, Olivia Mendivil, Rhodes, Adelaide C, Robertson, Helen E, Robertson, Hugh M, Ronshaugen, Matthew, Rozas, Julio, Saada, Nehad, Sánchez-Gracia, Alejandro, Scherer, Steven E, Schurko, Andrew M, Siggens, Kenneth W, Simmons, DeNard, Stief, Anna, Stolle, Eckart, Telford, Maximilian J, Tessmar-Raible, Kristin, Thornton, Rebecca, van der Zee, Maurijn, von Haeseler, Arndt, Williams, James M, Willis, Judith H, Wu, Yuanqing, and Zou, Xiaoyan
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Biotechnology, Prevention, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Animals, Arthropods, Circadian Rhythm Signaling Peptides and Proteins, DNA Methylation, Evolution, Molecular, Female, Genome, Genome, Mitochondrial, Hormones, Male, Multigene Family, Phylogeny, Polymorphism, Genetic, Protein Kinases, RNA, Untranslated, Receptors, Odorant, Selenoproteins, Sex Chromosomes, Synteny, Transcription Factors, Agricultural and Veterinary Sciences, Medical and Health Sciences, Developmental Biology, Agricultural, veterinary and food sciences, Biological sciences, Biomedical and clinical sciences
Abstract: Myriapods (e.g., centipedes and millipedes) display a simple homonomous body plan relative to other arthropods. All members of the class are terrestrial, but they attained terrestriality independently of insects. Myriapoda is the only arthropod class not represented by a sequenced genome. We present an analysis of the genome of the centipede Strigamia maritima. It retains a compact genome that has undergone less gene loss and shuffling than previously sequenced arthropods, and many orthologues of genes conserved from the bilaterian ancestor that have been lost in insects. Our analysis locates many genes in conserved macro-synteny contexts, and many small-scale examples of gene clustering. We describe several examples where S. maritima shows different solutions from insects to similar problems. The insect olfactory receptor gene family is absent from S. maritima, and olfaction in air is likely effected by expansion of other receptor gene families. For some genes S. maritima has evolved paralogues to generate coding sequence diversity, where insects use alternate splicing. This is most striking for the Dscam gene, which in Drosophila generates more than 100,000 alternate splice forms, but in S. maritima is encoded by over 100 paralogues. We see an intriguing linkage between the absence of any known photosensory proteins in a blind organism and the additional absence of canonical circadian clock genes. The phylogenetic position of myriapods allows us to identify where in arthropod phylogeny several particular molecular mechanisms and traits emerged. For example, we conclude that juvenile hormone signalling evolved with the emergence of the exoskeleton in the arthropods and that RR-1 containing cuticle proteins evolved in the lineage leading to Mandibulata. We also identify when various gene expansions and losses occurred. The genome of S. maritima offers us a unique glimpse into the ancestral arthropod genome, while also displaying many adaptations to its specific life history.
Published: 2014

28. Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis

Author: Chinn, Ivan K., Eckstein, Olive S., Peckham-Gregory, Erin C., Goldberg, Baruch R., Forbes, Lisa R., Nicholas, Sarah K., Mace, Emily M., Vogel, Tiphanie P., Abhyankar, Harshal A., Diaz, Maria I., Heslop, Helen E., Krance, Robert A., Martinez, Caridad A., Nguyen, Trung C., Bashir, Dalia A., Goldman, Jordana R., Stray-Pedersen, Asbjørg, Pedroza, Luis A., Poli, M. Cecilia, Aldave-Becerra, Juan C., McGhee, Sean A., Al-Herz, Waleed, Chamdin, Aghiad, Coban-Akdemir, Zeynep H., Jhangiani, Shalini N., Muzny, Donna M., Cao, Tram N., Hong, Diana N., Gibbs, Richard A., Lupski, James R., Orange, Jordan S., McClain, Kenneth L., and Allen, Carl E.
Published: 2018
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29. Insights into genetics, human biology and disease gleaned from family based genomic studies

Author: Posey, Jennifer E., O’Donnell-Luria, Anne H., Chong, Jessica X., Harel, Tamar, Jhangiani, Shalini N., Coban Akdemir, Zeynep H., Buyske, Steven, Pehlivan, Davut, Carvalho, Claudia M. B., Baxter, Samantha, Sobreira, Nara, Liu, Pengfei, Wu, Nan, Rosenfeld, Jill A., Kumar, Sushant, Avramopoulos, Dimitri, White, Janson J., Doheny, Kimberly F., Witmer, P. Dane, Boehm, Corinne, Sutton, V. Reid, Muzny, Donna M., Boerwinkle, Eric, Günel, Murat, Nickerson, Deborah A., Mane, Shrikant, MacArthur, Daniel G., Gibbs, Richard A., Hamosh, Ada, Lifton, Richard P., Matise, Tara C., Rehm, Heidi L., Gerstein, Mark, Bamshad, Michael J., Valle, David, Lupski, James R., and Centers for Mendelian Genomics
Published: 2019
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30. Genetic architecture of laterality defects revealed by whole exome sequencing

Author: Li, Alexander H., Hanchard, Neil A., Azamian, Mahshid, D’Alessandro, Lisa C. A., Coban-Akdemir, Zeynep, Lopez, Keila N., Hall, Nancy J., Dickerson, Heather, Nicosia, Annarita, Fernbach, Susan, Boone, Philip M., Gambin, Tomaz, Karaca, Ender, Gu, Shen, Yuan, Bo, Jhangiani, Shalini N., Doddapaneni, HarshaVardhan, Hu, Jianhong, Dinh, Huyen, Jayaseelan, Joy, Muzny, Donna, Lalani, Seema, Towbin, Jeffrey, Penny, Daniel, Fraser, Charles, Martin, James, Lupski, James R., Gibbs, Richard A., Boerwinkle, Eric, Ware, Stephanie M., and Belmont, John W.
Published: 2019
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31. The Drosophila melanogaster Genetic Reference Panel.

Author: Mackay, Trudy FC, Richards, Stephen, Stone, Eric A, Barbadilla, Antonio, Ayroles, Julien F, Zhu, Dianhui, Casillas, Sònia, Han, Yi, Magwire, Michael M, Cridland, Julie M, Richardson, Mark F, Anholt, Robert RH, Barrón, Maite, Bess, Crystal, Blankenburg, Kerstin Petra, Carbone, Mary Anna, Castellano, David, Chaboub, Lesley, Duncan, Laura, Harris, Zeke, Javaid, Mehwish, Jayaseelan, Joy Christina, Jhangiani, Shalini N, Jordan, Katherine W, Lara, Fremiet, Lawrence, Faye, Lee, Sandra L, Librado, Pablo, Linheiro, Raquel S, Lyman, Richard F, Mackey, Aaron J, Munidasa, Mala, Muzny, Donna Marie, Nazareth, Lynne, Newsham, Irene, Perales, Lora, Pu, Ling-Ling, Qu, Carson, Ràmia, Miquel, Reid, Jeffrey G, Rollmann, Stephanie M, Rozas, Julio, Saada, Nehad, Turlapati, Lavanya, Worley, Kim C, Wu, Yuan-Qing, Yamamoto, Akihiko, Zhu, Yiming, Bergman, Casey M, Thornton, Kevin R, Mittelman, David, and Gibbs, Richard A
Subjects: X Chromosome, Centromere, Telomere, Animals, Drosophila melanogaster, Starvation, Genomics, Genotype, Phenotype, Polymorphism, Single Nucleotide, Alleles, Quantitative Trait Loci, Genome-Wide Association Study, Selection, Genetic, Chromosomes, Insect, Chromosomes, Insect, Polymorphism, Single Nucleotide, Selection, Genetic, General Science & Technology
Abstract: A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype-phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype-phenotype mapping using the power of Drosophila genetics.
Published: 2012

32. Integrated sequencing and array comparative genomic hybridization in familial Parkinson disease

Author: Robak, Laurie A., Du, Renqian, Yuan, Bo, Gu, Shen, Alfradique-Dunham, Isabel, Kondapalli, Vismaya, Hinojosa, Evelyn, Stillwell, Amanda, Young, Emily, Zhang, Chaofan, Song, Xiaofei, Du, Haowei, Gambin, Tomasz, Jhangiani, Shalini N., Coban Akdemir, Zeynep, Muzny, Donna M., Tejomurtula, Anusha, Ross, Owen A., Shaw, Chad, Jankovic, Joseph, Bi, Weimin, Posey, Jennifer E., Lupski, James R., and Shulman, Joshua M.
Published: 2020
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33. Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis

Author: Du, Renqian, Dinckan, Nuriye, Song, Xiaofei, Coban-Akdemir, Zeynep, Jhangiani, Shalini N., Guven, Yeliz, Aktoren, Oya, Kayserili, Hulya, Petty, Lauren E., Muzny, Donna M., Below, Jennifer E., Boerwinkle, Eric, Wu, Nan, Gibbs, Richard A., Posey, Jennifer E., Lupski, James R., Letra, Ariadne, and Uyguner, Z. Oya
Published: 2018
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34. A novel NAA10 variant with impaired acetyltransferase activity causes developmental delay, intellectual disability, and hypertrophic cardiomyopathy

Author: Støve, Svein Isungset, Blenski, Marina, Stray-Pedersen, Asbjørg, Wierenga, Klaas J., Jhangiani, Shalini N., Akdemir, Zeynep Coban, Crawford, David, McTiernan, Nina, Myklebust, Line M., Purcarin, Gabriela, McNall-Knapp, Rene, Wadley, Alexandrea, Belmont, John W., Kim, Jeffrey J., Lupski, James R, and Arnesen, Thomas
Published: 2018
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35. Comprehensive genomic analysis of patients with disorders of cerebral cortical development

Author: Wiszniewski, Wojciech, Gawlinski, Pawel, Gambin, Tomasz, Bekiesinska-Figatowska, Monika, Obersztyn, Ewa, Antczak-Marach, Dorota, Akdemir, Zeynep Hande Coban, Harel, Tamar, Karaca, Ender, Jurek, Marta, Sobecka, Katarzyna, Nowakowska, Beata, Kruk, Malgorzata, Terczynska, Iwona, Goszczanska-Ciuchta, Alicja, Rudzka-Dybala, Mariola, Jamroz, Ewa, Pyrkosz, Antoni, Jakubiuk-Tomaszuk, Anna, Iwanowski, Piotr, Gieruszczak-Bialek, Dorota, Piotrowicz, Malgorzata, Sasiadek, Maria, Kochanowska, Iwona, Gurda, Barbara, Steinborn, Barbara, Dawidziuk, Mateusz, Castaneda, Jennifer, Wlasienko, Pawel, Bezniakow, Natalia, Jhangiani, Shalini N., Hoffman-Zacharska, Dorota, Bal, Jerzy, Szczepanik, Elzbieta, Boerwinkle, Eric, Gibbs, Richard A., and Lupski, James R.
Published: 2018
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36. Biallelic variants in KIF14 cause intellectual disability with microcephaly

Author: Makrythanasis, Periklis, Maroofian, Reza, Stray-Pedersen, Asbjørg, Musaev, Damir, Zaki, Maha S., Mahmoud, Iman G., Selim, Laila, Elbadawy, Amera, Jhangiani, Shalini N., Coban Akdemir, Zeynep H., Gambin, Tomasz, Sorte, Hanne S., Heiberg, Arvid, McEvoy-Venneri, Jennifer, James, Kiely N., Stanley, Valentina, Belandres, Denice, Guipponi, Michel, Santoni, Federico A., Ahangari, Najmeh, Tara, Fatemeh, Doosti, Mohammad, Iwaszkiewicz, Justyna, Zoete, Vincent, Backe, Paul Hoff, Hamamy, Hanan, Gleeson, Joseph G., Lupski, James R., Karimiani, Ehsan Ghayoor, and Antonarakis, Stylianos E.
Published: 2018
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37. Two male sibs with severe micrognathia and a missense variant in MED12

Author: Prescott, Trine E., Kulseth, Mari Ann, Heimdal, Ketil R., Stadheim, Barbro, Hopp, Einar, Gambin, Tomasz, Coban Akdemir, Zeynep H., Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Lupski, James R., and Stray-Pedersen, Asbjørg
Published: 2016
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38. Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome

Author: Carvalho, Claudia M. B., Coban-Akdemir, Zeynep, Hijazi, Hadia, Yuan, Bo, Pendleton, Matthew, Harrington, Eoghan, Beaulaurier, John, Juul, Sissel, Turner, Daniel J., Kanchi, Rupa S., Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Baylor-Hopkins Center for Mendelian Genomics, Stankiewicz, Pawel, Belmont, John W., Shaw, Chad A., Cheung, Sau Wai, Hanchard, Neil A., Sutton, V. Reid, Bader, Patricia I., and Lupski, James R.
Published: 2019
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39. Biallelic missense variants in COG3 cause a congenital disorder of glycosylation with impairment of retrograde vesicular trafficking.

Author: Duan, Ruizhi, Marafi, Dana, Xia, Zhi‐Jie, Ng, Bobby G., Maroofian, Reza, Sumya, Farhana Taher, Saad, Ahmed K., Du, Haowei, Fatih, Jawid M., Hunter, Jill V., Elbendary, Hasnaa M., Baig, Shahid M., Abdullah, Uzma, Ali, Zafar, Efthymiou, Stephanie, Murphy, David, Mitani, Tadahiro, Withers, Marjorie A., Jhangiani, Shalini N., and Coban‐Akdemir, Zeynep
Abstract: Biallelic variants in genes for seven out of eight subunits of the conserved oligomeric Golgi complex (COG) are known to cause recessive congenital disorders of glycosylation (CDG) with variable clinical manifestations. COG3 encodes a constituent subunit of the COG complex that has not been associated with disease traits in humans. Herein, we report two COG3 homozygous missense variants in four individuals from two unrelated consanguineous families that co‐segregated with COG3–CDG presentations. Clinical phenotypes of affected individuals include global developmental delay, severe intellectual disability, microcephaly, epilepsy, facial dysmorphism, and variable neurological findings. Biochemical analysis of serum transferrin from one family showed the loss of a single sialic acid. Western blotting on patient‐derived fibroblasts revealed reduced COG3 and COG4. Further experiments showed delayed retrograde vesicular recycling in patient cells. This report adds to the knowledge of the COG–CDG network by providing collective evidence for a COG3–CDG rare disease trait and implicating a likely pathology of the disorder as the perturbation of Golgi trafficking. [ABSTRACT FROM AUTHOR]
Published: 2023
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40. Novel LSS variants in alopecia and intellectual disability syndrome: New case report and clinical spectrum of LSS‐related rare disease traits.

Author: Elbendary, Hasnaa M., Marafi, Dana, Saad, Ahmed K., Elhossini, Rasha, Duan, Ruizhi, Rafat, Karima, Jhangiani, Shalini N., Gibbs, Richard A., Pehlivan, Davut, Calame, Daniel G., Posey, Jennifer E., Lupski, James R., and Zaki, Maha S.
Subjects: INTELLECTUAL disabilities, RARE diseases, AGENESIS of corpus callosum, BALDNESS, SYNDROMES, CEREBRAL atrophy, FRAGILE X syndrome
Abstract: Pathogenic biallelic variants in LSS are associated with three Mendelian rare disease traits including congenital cataract type 44, autosomal recessive hypotrichosis type 14, and alopecia‐intellectual disability syndrome type 4 (APMR4). We performed trio research exome sequencing on a family with a four‐year‐old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variant alleles. Rare features associated with APMR4 such as cryptorchidism, micropenis, mild cortical brain atrophy and thin corpus callosum were detected. Previously unreported APMR4 findings including cerebellar involvement in the form of unsteady ataxic gait, small vermis with prominent folia, were noted. A review of all reported variants to date in 29 families with LSS‐related phenotypes showed an emerging genotype–phenotype correlation. Our report potentially expands LSS‐related phenotypic spectrum and highlights the importance of performing brain imaging in LSS‐related conditions. [ABSTRACT FROM AUTHOR]
Published: 2023
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41. Biallelic mutations in IRF8 impair human NK cell maturation and function

Author: Mace, Emily M., Bigley, Venetia, Gunesch, Justin T., Chinn, Ivan K., Angelo, Laura S., Care, Matthew A., Maisuria, Sheetal, Keller, Michael D., Togi, Sumihito, Watkin, Levi B., LaRosa, David F., Jhangiani, Shalini N., Muzny, Donna M., Stray- Pedersen, Asbjorg, Akdemir, Zeynep Coban, Smith, Jansen B., Hernandez-Sanabria, Mayra, Le, Duy T., Hogg, Graham D., Cao, Tram N., Freud, Aharon G., Szymanski, Eva P., Savic, Sinisa, Collin, Matthew, Cant, Andrew J., Gibbs, Richard A., Holland, Steven M., Caligiuri, Michael A., Ozato, Keiko, Paust, Silke, Doody, Gina M., Lupski, James R., and Orange, Jordan S.
Subjects: Nucleotide sequencing -- Usage, Gene mutations -- Analysis, DNA sequencing -- Usage, Killer cells -- Analysis, Health care industry
Abstract: Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease. Compound heterozygous or homozygous mutations in IRF8 in 3 unrelated families resulted in a paucity of mature [CD56.sup.dim] NK cells and an increase in the frequency of the immature [CD56.sub.bright] NK cells, and this impairment in terminal maturation was also observed in [Irf8.sup.-/-], but not [Irf8.sup.+/-] mice. We then determined that impaired maturation was NK cell intrinsic, and gene expression analysis of human NK cell developmental subsets showed that multiple genes were dysregulated by IRF8 mutation. The phenotype was accompanied by deficient NK cell function and was stable over time. Together, these data indicate that human NK cells require IRF8 for development and functional maturation and that dysregulation of this function results in severe human disease, thereby emphasizing a critical role for NK cells in human antiviral defense., Introduction NK cell deficiency (NKD) is an inborn or primary immunodeficiency causing susceptibility to severe and often fatal viral infection and malignancy (1-5). NKD can be classified as classical, arising [...]
Published: 2017
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42. The sheep genome illuminates biology of the rumen and lipid metabolism

Author: Jiang, Yu, Xie, Min, Chen, Wenbin, Talbot, Richard, Maddox, Jillian F., Faraut, Thomas, Wu, Chunhua, Muzny, Donna M., Li, Yuxiang, Zhang, Wenguang, Stanton, Jo-Ann, Brauning, Rudiger, Barris, Wesley C., Hourlier, Thibaut, Aken, Bronwen L., Searle, Stephen M. J., Adelson, David L., Bian, Chao, Cam, Graham R., Chen, Yulin, Cheng, Shifeng, DeSilva, Udaya, Dixen, Karen, Dong, Yang, Fan, Guangyi, Franklin, Ian R., Fu, Shaoyin, Fuentes-Utrilla, Pablo, Guan, Rui, Highland, Margaret A., Holder, Michael E., Huang, Guodong, Ingham, Aaron B., Jhangiani, Shalini N., Kalra, Divya, Kovar, Christie L., Lee, Sandra L., Liu, Weiqing, Liu, Xin, Lu, Changxin, Lv, Tian, Mathew, Tittu, McWilliam, Sean, Menzies, Moira, Pan, Shengkai, Robelin, David, Servin, Bertrand, Townley, David, Wang, Wenliang, Wei, Bin, White, Stephen N., Yang, Xinhua, Ye, Chen, Yue, Yaojing, Zeng, Peng, Zhou, Qing, Hansen, Jacob B., Kristiansen, Karsten, Gibbs, Richard A., Flicek, Paul, Warkup, Christopher C., Jones, Huw E., Oddy, V. Hutton, Nicholas, Frank W., McEwan, John C., Kijas, James W., Wang, Jun, Worley, Kim C., Archibald, Alan L., Cockett, Noelle, Xu, Xun, Wang, Wen, and Dalrymple, Brian P.
Published: 2014

43. Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Author: Bayram, Yavuz, Karaca, Ender, Akdemir, Zeynep Coban, Yilmaz, Elif Ozdamar, Tayfun, Gulsen Akay, Aydin, Hatip, Torun, Deniz, Bozdogan, Sevcan Tug, Gezdirici, Alper, Isikay, Sedat, Atik, Mehmed M., Gambin, Tomasz, Harel, Tamar, El-Hattab, Ayman W., Charng, Wu-Lin, Pehlivan, Davut, Jhangiani, Shalini N., Muzny, Donna M., Karaman, Ali, Celik, Tamer, Yuregir, Ozge Ozalp, Yildirim, Timur, Bayhan, Ilhan A., Boerwinkle, Eric, Gibbs, Richard A., Elcioglu, Nursel, Tuysuz, Beyhan, and Lupski, James R.
Subjects: Arthrogryposis -- Genetic aspects -- Development and progression, Gene expression -- Health aspects, Exome sequencing -- Methods, Genotype -- Identification and classification, Health care industry
Abstract: BACKGROUND. Arthrogryposis, defined as congenital joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases. METHODS. We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families. RESULTS. Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic y nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme-like 1 (ECEL1, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 [FBNS], myosin IXA [MYO9A], and pleckstrin and Sec7 domain containing 3 [PSDS]) were identified in 3 families (6.2%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis-associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type [MYBPC2] and vacuolar protein sorting 8 [UPSS], 2 families, 4.2%) or in another disease-associated genes (6 families, 12.5%), indicating a potential mutational burden contributing to disease expression. CONCLUSION. In 58.3% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically heterogeneous disorders, such as arthrogryposis. FUNDING. This work was supported in part by US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 to J.R. Lupski., Introduction Arthrogryposis, also known as arthrogryposis multiplex congenita, is clinically defined as congenital joint contractures or movement restriction in multiple body areas. It should be distinguished from isolated congenital contractures [...]
Published: 2016
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44. Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

Author: Szafranski, Przemyslaw, Gambin, Tomasz, Dharmadhikari, Avinash V., Akdemir, Kadir Caner, Jhangiani, Shalini N., Schuette, Jennifer, Godiwala, Nihal, Yatsenko, Svetlana A., Sebastian, Jessica, Madan-Khetarpal, Suneeta, Surti, Urvashi, Abellar, Rosanna G., Bateman, David A., Wilson, Ashley L., Markham, Melinda H., Slamon, Jill, Santos-Simarro, Fernando, Palomares, María, Nevado, Julián, Lapunzina, Pablo, Chung, Brian Hon-Yin, Wong, Wai-Lap, Chu, Yoyo Wing Yiu, Mok, Gary Tsz Kin, Kerem, Eitan, Reiter, Joel, Ambalavanan, Namasivayam, Anderson, Scott A., Kelly, David R., Shieh, Joseph, Rosenthal, Taryn C., Scheible, Kristin, Steiner, Laurie, Iqbal, M. Anwar, McKinnon, Margaret L., Hamilton, Sara Jane, Schlade-Bartusiak, Kamilla, English, Dawn, Hendson, Glenda, Roeder, Elizabeth R., DeNapoli, Thomas S., Littlejohn, Rebecca Okashah, Wolff, Daynna J., Wagner, Carol L., Yeung, Alison, Francis, David, Fiorino, Elizabeth K., Edelman, Morris, Fox, Joyce, Hayes, Denise A., Janssens, Sandra, De Baere, Elfride, Menten, Björn, Loccufier, Anne, Vanwalleghem, Lieve, Moerman, Philippe, Sznajer, Yves, Lay, Amy S., Kussmann, Jennifer L., Chawla, Jasneek, Payton, Diane J., Phillips, Gael E., Brosens, Erwin, Tibboel, Dick, de Klein, Annelies, Maystadt, Isabelle, Fisher, Richard, Sebire, Neil, Male, Alison, Chopra, Maya, Pinner, Jason, Malcolm, Girvan, Peters, Gregory, Arbuckle, Susan, Lees, Melissa, Mead, Zoe, Quarrell, Oliver, Sayers, Richard, Owens, Martina, Shaw-Smith, Charles, Lioy, Janet, McKay, Eileen, de Leeuw, Nicole, Feenstra, Ilse, Spruijt, Liesbeth, Elmslie, Frances, Thiruchelvam, Timothy, Bacino, Carlos A., Langston, Claire, Lupski, James R., Sen, Partha, Popek, Edwina, and Stankiewicz, Paweł
Published: 2016
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45. Dual molecular diagnosis contributes to atypical Prader–Willi phenotype in monozygotic twins

Author: Jehee, Fernanda S., de Oliveira, Valdirene T., Gurgel‐Giannetti, Juliana, Pietra, Rafaella X., Rubatino, Fernando V. M., Carobin, Natália V., Vianna, Gabrielle S., de Freitas, Mariana L., Fernandes, Karla S., Ribeiro, Beatriz S. V., Brüggenwirth, Hennie T., Ali‐Amin, Roza, White, Janson J., Akdemir, Zeynep C., Jhangiani, Shalini N., Gibbs, Richard A., Lupski, James R., Varela, Monica C., Koiffmann, Célia, Rosenberg, Carla, and Carvalho, Cláudia M. B.
Published: 2017
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46. A biallelic frameshift indel in PPP1R35 as a cause of primary microcephaly.

Author: Dawood, Moez, Akay, Gulsen, Mitani, Tadahiro, Marafi, Dana, Fatih, Jawid M., Gezdirici, Alper, Najmabadi, Hossein, Kahrizi, Kimia, Punetha, Jaya, Grochowski, Christopher M., Du, Haowei, Jolly, Angad, Li, He, Coban‐Akdemir, Zeynep, Sedlazeck, Fritz J., Hunter, Jill V., Jhangiani, Shalini N., Muzny, Donna, Pehlivan, Davut, and Posey, Jennifer E.
Abstract: Protein phosphatase 1 regulatory subunit 35 (PPP1R35) encodes a centrosomal protein required for recruiting microtubule‐binding elongation machinery. Several proteins in this centriole biogenesis pathway correspond to established primary microcephaly (MCPH) genes, and multiple model organism studies hypothesize PPP1R35 as a candidate MCPH gene. Here, using exome sequencing (ES) and family‐based rare variant analyses, we report a homozygous, frameshifting indel deleting the canonical stop codon in the last exon of PPP1R35 [Chr7: c.753_*3delGGAAGCGTAGACCinsCG (p.Trp251Cysfs*22)]; the variant allele maps in a 3.7 Mb block of absence of heterozygosity (AOH) in a proband with severe MCPH (−4.3 SD at birth, −6.1 SD by 42 months), pachygyria, and global developmental delay from a consanguineous Turkish kindred. Droplet digital PCR (ddPCR) confirmed mutant mRNA expression in fibroblasts. In silico prediction of the translation of mutant PPP1R35 is expected to be elongated by 18 amino acids before encountering a downstream stop codon. This complex indel allele is absent in public databases (ClinVar, gnomAD, ARIC, 1000 genomes) and our in‐house database of 14,000+ exomes including 1800+ Turkish exomes supporting predicted pathogenicity. Comprehensive literature searches for PPP1R35 variants yielded two probands affected with severe microcephaly (−15 SD and −12 SD) with the same homozygous indel from a single, consanguineous, Iranian family from a cohort of 404 predominantly Iranian families. The lack of heterozygous cases in two large cohorts representative of the genetic background of these two families decreased our suspicion of a founder allele and supports the contention of a recurrent mutation. We propose two potential secondary structure mutagenesis models for the origin of this variant allele mediated by hairpin formation between complementary GC rich segments flanking the stop codon via secondary structure mutagenesis. [ABSTRACT FROM AUTHOR]
Published: 2023
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47. Epistasis dominates the genetic architecture of Drosophila quantitative traits

Author: Huang, Wen, Richards, Stephen, Carbone, Mary Anna, Zhu, Dianhui, Anholt, Robert R. H., Ayroles, Julien F., Duncan, Laura, Jordan, Katherine W., Lawrence, Faye, Magwire, Michael M., Warner, Crystal B., Blankenburg, Kerstin, Han, Yi, Javaid, Mehwish, Jayaseelan, Joy, Jhangiani, Shalini N., Muzny, Donna, Ongeri, Fiona, Perales, Lora, Wu, Yuan-Qing, Zhang, Yiqing, Zou, Xiaoyan, Stone, Eric A., Gibbs, Richard A., and Mackay, Trudy F. C.
Published: 2012

48. Germline Mutations in Shelterin Complex Genes Are Associated With Familial Glioma

Author: Bainbridge, Matthew N., Armstrong, Georgina N., Gramatges, M. Monica, Bertuch, Alison A., Jhangiani, Shalini N., Doddapaneni, Harsha, Lewis, Lora, Tombrello, Joseph, Tsavachidis, Spyros, Liu, Yanhong, Jalali, Ali, Plon, Sharon E., Lau, Ching C., Parsons, Donald W., Claus, Elizabeth B., Barnholtz-Sloan, Jill, Il’yasova, Dora, Schildkraut, Joellen, Ali-Osman, Francis, Sadetzki, Siegal, Johansen, Christoffer, Houlston, Richard S., Jenkins, Robert B., Lachance, Daniel, Olson, Sara H., Bernstein, Jonine L., Merrell, Ryan T., Wrensch, Margaret R., Walsh, Kyle M., Davis, Faith G., Lai, Rose, Shete, Sanjay, Aldape, Kenneth, Amos, Christopher I., Thompson, Patricia A., Muzny, Donna M., Gibbs, Richard A., Melin, Beatrice S., and Bondy, Melissa L.
Published: 2015
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49. 2C DNA CONTENT VALUES IN AMARANTHUS (AMARANTHACEAE)

Author: Pratt, Donald B., Jhangiani, Shalini N., and Wiggers, Robert J.
Published: 2008

50. Compound Heterozygous CORO1A Mutations in Siblings with a Mucocutaneous-Immunodeficiency Syndrome of Epidermodysplasia Verruciformis-HPV, Molluscum Contagiosum and Granulomatous Tuberculoid Leprosy

Author: Stray-Pedersen, Asbjorg, Jouanguy, Emmanuelle, Crequer, Amandine, Bertuch, Alison A., Brown, Betty S., Jhangiani, Shalini N., Muzny, Donna M., Gambin, Tomasz, Sorte, Hanne, Sasa, Ghadir, Metry, Denise, Campbell, Judith, Sockrider, Marianna M., Dishop, Megan K., Scollard, David M., Gibbs, Richard A., Mace, Emily M., Orange, Jordan S., Lupski, James R., Casanova, Jean-Laurent, and Noroski, Lenora M.
Published: 2014
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