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1. 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

2. Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome

Author

Blue, Elizabeth E., White, Janson J., Dush, Michael K., Gordon, William W., Wyatt, Brent H., White, Peter, Marvin, Colby T., Helle, Emmi, Ojala, Tiina, Priest, James R., Jenkins, Mary M., Almli, Lynn M., Reefhuis, Jennita, Pangilinan, Faith, Brody, Lawrence C., McBride, Kim L., Garg, Vidu, Shaw, Gary M., Romitti, Paul A., Nembhard, Wendy N., Browne, Marilyn L., Werler, Martha M., Kay, Denise M., Mital, Seema, Chong, Jessica X., Nascone-Yoder, Nanette M., and Bamshad, Michael J.

Published
2023
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3. Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study.

Author

Blue, Elizabeth E., Moore, Kristin J., North, Kari E., Desrosiers, Tania A., Carmichael, Suzan L., White, Janson J., Chong, Jessica X., Bamshad, Michael J., Jenkins, Mary M., Almli, Lynn M., Brody, Lawrence C., Freedman, Sharon F., Reefhuis, Jennita, Romitti, Paul A., Shaw, Gary M., Werler, Martha, Kay, Denise M., Browne, Marilyn L., Feldkamp, Marcia L., and Finnell, Richard H.

Abstract

Background: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants. Methods: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997–2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI. Results: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2). Conclusion: Variation in the genes identified in this population‐based study may help to further explain the genetics of PCG. [ABSTRACT FROM AUTHOR]

Published
2024
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4. 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

5. 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

7. 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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8. De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease

Author

Ma, Lijiang, Bayram, Yavuz, McLaughlin, Heather M., Cho, Megan T., Krokosky, Alyson, Turner, Clesson E., Lindstrom, Kristin, Bupp, Caleb P., Mayberry, Katey, Mu, Weiyi, Bodurtha, Joann, Weinstein, Veronique, Zadeh, Neda, Alcaraz, Wendy, Powis, Zöe, Shao, Yunru, Scott, Daryl A., Lewis, Andrea M., White, Janson J., Jhangiani, Shalani N., Gulec, Elif Yilmaz, Lalani, Seema R., Lupski, James R., Retterer, Kyle, Schnur, Rhonda E., Wentzensen, Ingrid M., Bale, Sherri, and Chung, Wendy K.

Published
2016
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9. Back Cover, Volume 43, Issue 7

Author

Lima, Ariadne R., primary, Ferreira, Barbara M., additional, Zhang, Chaofan, additional, Jolly, Angad, additional, Du, Haowei, additional, White, Janson J., additional, Dawood, Moez, additional, Lins, Tulio C., additional, Chiabai, Marcela A., additional, van Beusekom, Ellen, additional, Cordoba, Mara S., additional, Caldas Rosa, Erica C.C., additional, Kayserili, Hulya, additional, Kimonis, Virginia, additional, Wu, Erica, additional, Mellado, Cecilia, additional, Aggarwal, Vineet, additional, Richieri‐Costa, Antonio, additional, Brunoni, Décio, additional, Canó, Talyta M., additional, Jorge, Alexander A. L., additional, Kim, Chong A., additional, Honjo, Rachel, additional, Bertola, Débora R., additional, Dandalo‐Girardi, Raissa M., additional, Bayram, Yavuz, additional, Gezdirici, Alper, additional, Yilmaz‐Gulec, Elif, additional, Gumus, Evren, additional, Yilmaz, Gülay C., additional, Okamoto, Nobuhiko, additional, Ohashi, Hirofumi, additional, Coban–Akdemir, Zeynep, additional, Mitani, Tadahiro, additional, Jhangiani, Shalini N., additional, Muzny, Donna M., additional, Regattieri, Neysa A.P., additional, Pogue, Robert, additional, Pereira, Rinaldo W., additional, Otto, Paulo A., additional, Gibbs, Richard A., additional, Ali, Bassam R., additional, van Bokhoven, Hans, additional, Brunner, Han G., additional, Sutton, V. Reid, additional, Lupski, James R., additional, Vianna‐Morgante, Angela M., additional, Carvalho, Claudia M. B., additional, and Mazzeu, Juliana F., additional

Published
2022
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10. Centers for Mendelian Genomics: A decade of facilitating gene discovery

Author

Baxter, Samantha M., primary, Posey, Jennifer E., additional, Lake, Nicole J., additional, Sobreira, Nara, additional, Chong, Jessica X., additional, Buyske, Steven, additional, Blue, Elizabeth E., additional, Chadwick, Lisa H., additional, Coban-Akdemir, Zeynep H., additional, Doheny, Kimberly F., additional, Davis, Colleen P., additional, Lek, Monkol, additional, Wellington, Christopher, additional, Jhangiani, Shalini N., additional, Gerstein, Mark, additional, Gibbs, Richard A., additional, Lifton, Richard P., additional, MacArthur, Daniel G., additional, Matise, Tara C., additional, Lupski, James R., additional, Valle, David, additional, Bamshad, Michael J., additional, Hamosh, Ada, additional, Mane, Shrikant, additional, Nickerson, Deborah A., additional, Rehm, Heidi L., additional, O’Donnell-Luria, Anne, additional, Adams, Marcia, additional, Aguet, François, additional, Akay, Gulsen, additional, Anderson, Peter, additional, Antonescu, Corina, additional, Arachchi, Harindra M., additional, Atik, Mehmed M., additional, Austin-Tse, Christina A., additional, Babb, Larry, additional, Bacus, Tamara J., additional, Bahrambeigi, Vahid, additional, Balasubramanian, Suganthi, additional, Bayram, Yavuz, additional, Beaudet, Arthur L., additional, Beck, Christine R., additional, Belmont, John W., additional, Below, Jennifer E., additional, Bilguvar, Kaya, additional, Boehm, Corinne D., additional, Boerwinkle, Eric, additional, Boone, Philip M., additional, Bowne, Sara J., additional, Brand, Harrison, additional, Buckingham, Kati J., additional, Byrne, Alicia B., additional, Calame, Daniel, additional, Campbell, Ian M., additional, Cao, Xiaolong, additional, Carvalho, Claudia, additional, Chander, Varuna, additional, Chang, Jaime, additional, Chao, Katherine R., additional, Chinn, Ivan K., additional, Clarke, Declan, additional, Collins, Ryan L., additional, Cummings, Beryl, additional, Dardas, Zain, additional, Dawood, Moez, additional, Delano, Kayla, additional, DiTroia, Stephanie P., additional, Doddapaneni, Harshavardhan, additional, Du, Haowei, additional, Du, Renqian, additional, Duan, Ruizhi, additional, Eldomery, Mohammad, additional, Eng, Christine M., additional, England, Eleina, additional, Evangelista, Emily, additional, Everett, Selin, additional, Fatih, Jawid, additional, Felsenfeld, Adam, additional, Francioli, Laurent C., additional, Frazar, Christian D., additional, Fu, Jack, additional, Gamarra, Emmanuel, additional, Gambin, Tomasz, additional, Gan, Weiniu, additional, Gandhi, Mira, additional, Ganesh, Vijay S., additional, Garimella, Kiran V., additional, Gauthier, Laura D., additional, Giroux, Danielle, additional, Gonzaga-Jauregui, Claudia, additional, Goodrich, Julia K., additional, Gordon, William W., additional, Griffith, Sean, additional, Grochowski, Christopher M., additional, Gu, Shen, additional, Gudmundsson, Sanna, additional, Hall, Stacey J., additional, Hansen, Adam, additional, Harel, Tamar, additional, Harmanci, Arif O., additional, Herman, Isabella, additional, Hetrick, Kurt, additional, Hijazi, Hadia, additional, Horike-Pyne, Martha, additional, Hsu, Elvin, additional, Hu, Jianhong, additional, Huang, Yongqing, additional, Hurless, Jameson R., additional, Jahl, Steve, additional, Jarvik, Gail P., additional, Jiang, Yunyun, additional, Johanson, Eric, additional, Jolly, Angad, additional, Karaca, Ender, additional, Khayat, Michael, additional, Knight, James, additional, Kolar, J. Thomas, additional, Kumar, Sushant, additional, Lalani, Seema, additional, Laricchia, Kristen M., additional, Larkin, Kathryn E., additional, Leal, Suzanne M., additional, Lemire, Gabrielle, additional, Lewis, Richard A., additional, Li, He, additional, Ling, Hua, additional, Lipson, Rachel B., additional, Liu, Pengfei, additional, Lovgren, Alysia Kern, additional, López-Giráldez, Francesc, additional, MacMillan, Melissa P., additional, Mangilog, Brian E., additional, Mano, Stacy, additional, Marafi, Dana, additional, Marosy, Beth, additional, Marshall, Jamie L., additional, Martin, Renan, additional, Marvin, Colby T., additional, Mawhinney, Michelle, additional, McGee, Sean, additional, McGoldrick, Daniel J., additional, Mehaffey, Michelle, additional, Mekonnen, Betselote, additional, Meng, Xiaolu, additional, Mitani, Tadahiro, additional, Miyake, Christina Y., additional, Mohr, David, additional, Morris, Shaine, additional, Mullen, Thomas E., additional, Murdock, David R., additional, Murugan, Mullai, additional, Muzny, Donna M., additional, Myers, Ben, additional, Neira, Juanita, additional, Nguyen, Kevin K., additional, Nielsen, Patrick M., additional, Nudelman, Natalie, additional, O’Heir, Emily, additional, O’Leary, Melanie C., additional, Ongaco, Chrissie, additional, Orange, Jordan, additional, Osei-Owusu, Ikeoluwa A., additional, Paine, Ingrid S., additional, Pais, Lynn S., additional, Paschall, Justin, additional, Patterson, Karynne, additional, Pehlivan, Davut, additional, Pelle, Benjamin, additional, Penney, Samantha, additional, Perez de Acha Chavez, Jorge, additional, Pierce-Hoffman, Emma, additional, Poli, Cecilia M., additional, Punetha, Jaya, additional, Radhakrishnan, Aparna, additional, Richardson, Matthew A., additional, Rodrigues, Eliete, additional, Roote, Gwendolin T., additional, Rosenfeld, Jill A., additional, Ryke, Erica L., additional, Sabo, Aniko, additional, Sanchez, Alice, additional, Schrauwen, Isabelle, additional, Scott, Daryl A., additional, Sedlazeck, Fritz, additional, Serrano, Jillian, additional, Shaw, Chad A., additional, Shelford, Tameka, additional, Shively, Kathryn M., additional, Singer-Berk, Moriel, additional, Smith, Joshua D., additional, Snow, Hana, additional, Snyder, Grace, additional, Solomonson, Matthew, additional, Son, Rachel G., additional, Song, Xiaofei, additional, Stankiewicz, Pawel, additional, Stephan, Taylorlyn, additional, Sutton, V. Reid, additional, Sveden, Abigail, additional, Sánchez, Diana Cornejo, additional, Tackett, Monica, additional, Talkowski, Michael, additional, Threlkeld, Machiko S., additional, Tiao, Grace, additional, Udler, Miriam S., additional, Vail, Laura, additional, Valivullah, Zaheer, additional, Valkanas, Elise, additional, VanNoy, Grace E., additional, Wang, Qingbo S., additional, Wang, Gao, additional, Wang, Lu, additional, Wangler, Michael F., additional, Watts, Nicholas A., additional, Weisburd, Ben, additional, Weiss, Jeffrey M., additional, Wheeler, Marsha M., additional, White, Janson J., additional, Williamson, Clara E., additional, Wilson, Michael W., additional, Wiszniewski, Wojciech, additional, Withers, Marjorie A., additional, Witmer, Dane, additional, Witzgall, Lauren, additional, Wohler, Elizabeth, additional, Wojcik, Monica H., additional, Wong, Isaac, additional, Wood, Jordan C., additional, Wu, Nan, additional, Xing, Jinchuan, additional, Yang, Yaping, additional, Yi, Qian, additional, Yuan, Bo, additional, Zeiger, Jordan E., additional, Zhang, Chaofan, additional, Zhang, Peng, additional, Zhang, Yan, additional, Zhang, Xiaohong, additional, Zhang, Yeting, additional, Zhang, Shifa, additional, Zoghbi, Huda, additional, and van den Veyver, Igna, additional

Published
2022
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11. 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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12. Whole-Exome Sequencing in Familial Parkinson Disease

Author

Farlow, Janice L., Robak, Laurie A., Hetrick, Kurt, Bowling, Kevin, Boerwinkle, Eric, Coban-Akdemir, Zeynep H., Gambin, Tomasz, Gibbs, Richard A., Gu, Shen, Jain, Preti, Jankovic, Joseph, Jhangiani, Shalini, Kaw, Kaveeta, Lai, Dongbing, Lin, Hai, Ling, Hua, Liu, Yunlong, Lupski, James R., Muzny, Donna, Porter, Paula, Pugh, Elizabeth, White, Janson, Doheny, Kimberly, Myers, Richard M., Shulman, Joshua M., and Foroud, Tatiana

Published
2016
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13. Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome

Author

Zhang, Chaofan, primary, Mazzeu, Juliana F., additional, Eisfeldt, Jesper, additional, Grochowski, Christopher M., additional, White, Janson, additional, Akdemir, Zeynep C., additional, Jhangiani, Shalini N., additional, Muzny, Donna M., additional, Gibbs, Richard A., additional, Lindstrand, Anna, additional, Lupski, James R., additional, Sutton, V. Reid, additional, and Carvalho, Claudia M. B., additional

Published
2020
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14. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

Author

Mirzaa, Ghayda M., primary, Chong, Jessica X., additional, Piton, Amélie, additional, Popp, Bernt, additional, Foss, Kimberly, additional, Guo, Hui, additional, Harripaul, Ricardo, additional, Xia, Kun, additional, Scheck, Joshua, additional, Aldinger, Kimberly A., additional, Sajan, Samin A., additional, Tang, Sha, additional, Bonneau, Dominique, additional, Beck, Anita, additional, White, Janson, additional, Mahida, Sonal, additional, Harris, Jacqueline, additional, Smith-Hicks, Constance, additional, Hoyer, Juliane, additional, Zweier, Christiane, additional, Reis, André, additional, Thiel, Christian T., additional, Jamra, Rami Abou, additional, Zeid, Natasha, additional, Yang, Amy, additional, Farach, Laura S., additional, Walsh, Laurence, additional, Payne, Katelyn, additional, Rohena, Luis, additional, Velinov, Milen, additional, Ziegler, Alban, additional, Schaefer, Elise, additional, Gatinois, Vincent, additional, Geneviève, David, additional, Simon, Marleen E.H., additional, Kohler, Jennefer, additional, Rotenberg, Joshua, additional, Wheeler, Patricia, additional, Larson, Austin, additional, Ernst, Michelle E., additional, Akman, Cigdem I., additional, Westman, Rachel, additional, Blanchet, Patricia, additional, Schillaci, Lori-Anne, additional, Vincent-Delorme, Catherine, additional, Gripp, Karen W., additional, Mattioli, Francesca, additional, Guyader, Gwenaël Le, additional, Gerard, Bénédicte, additional, Mathieu-Dramard, Michèle, additional, Morin, Gilles, additional, Sasanfar, Roksana, additional, Ayub, Muhammad, additional, Vasli, Nasim, additional, Yang, Sandra, additional, Person, Rick, additional, Monaghan, Kristin G., additional, Nickerson, Deborah A., additional, van Binsbergen, Ellen, additional, Enns, Gregory M., additional, Dries, Annika M., additional, Rowe, Leah J., additional, Tsai, Anne C.H., additional, Svihovec, Shayna, additional, Friedman, Jennifer, additional, Agha, Zehra, additional, Qamar, Raheel, additional, Rodan, Lance H., additional, Martinez-Agosto, Julian, additional, Ockeloen, Charlotte W., additional, Vincent, Marie, additional, Sunderland, William James, additional, Bernstein, Jonathan A., additional, Eichler, Evan E., additional, Vincent, John B., additional, and Bamshad, Michael J., additional

Published
2020
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15. Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome.

Author

Zhang, Chaofan, Mazzeu, Juliana F., Eisfeldt, Jesper, Grochowski, Christopher M., White, Janson, Akdemir, Zeynep C., Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Lindstrand, Anna, Lupski, James R., Sutton, V. Reid, and Carvalho, Claudia M. B.

Abstract

Robinow syndrome (RS) is a genetically heterogeneous disorder characterized by skeletal dysplasia and a distinctive facial appearance. Previous studies have revealed locus heterogeneity with rare variants in DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A underlying the etiology of RS. The aforementioned "Robinow‐associated genes" and their gene products all play a role in the WNT/planar cell polarity signaling pathway. We performed gene‐targeted Sanger sequencing, exome sequencing, genome sequencing, and array comparative genomic hybridization on four subjects with a clinical diagnosis of RS who had not had prior DNA testing. Individuals in our cohort were found to carry pathogenic or likely pathogenic variants in three RS related genes: DVL1, ROR2, and NXN. One subject was found to have a nonsense variant (c.817C > T [p.Gln273*]) in NXN in trans with an ~1 Mb telomeric deletion on chromosome 17p containing NXN, which supports our contention that biallelic NXN variant alleles are responsible for a novel autosomal recessive RS locus. These findings provide increased understanding of the role of WNT signaling in skeletal development and maintenance. These data further support the hypothesis that dysregulation of the noncanonical WNT pathway in humans gives rise to RS. [ABSTRACT FROM AUTHOR]

Published
2021
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16. Further delineation of van den Ende‐Gupta syndrome: Genetic heterogeneity and overlap with congenital heart defects and skeletal malformations syndrome.

Author

Hildebrandt, Clara C., Patel, Nisha, Graham, John M., Bamshad, Michael, Nickerson, Deborah A., White, Janson J., Marvin, Colby T., Miller, Danny E., Grand, Katheryn L., Sanchez‐Lara, Pedro A., Schweitzer, Daniela, Al‐Zaidan, Hamad I., Al Masseri, Zainab, Alkuraya, Fowzan S., and Lin, Angela E.

Abstract

Van den Ende‐Gupta syndrome (VDEGS) is a rare autosomal recessive condition characterized by distinctive facial and skeletal features, and in most affected persons, by biallelic pathogenic variants in SCARF2. We review the type and frequency of the clinical features in 36 reported individuals with features of VDEGS, 15 (42%) of whom had known pathogenic variants in SCARF2, 6 (16%) with negative SCARF2 testing, and 15 (42%) not tested. We also report three new individuals with pathogenic variants in SCARF2 and clinical features of VDEGS. Of the six persons without known pathogenic variants in SCARF2, three remain unsolved despite extensive genetic testing. Three were found to have pathogenic ABL1 variants using whole exome sequencing (WES) or whole genome sequencing (WGS). Their phenotype was consistent with the congenital heart disease and skeletal malformations syndrome (CHDSKM), which has been associated with ABL1 variants. Of the three unsolved cases, two were brothers who underwent WGS and targeted long‐range sequencing of both SCARF2 and ABL1, and the third person who underwent WES and RNA sequencing for SCARF2. Because these affected individuals with classical features of VDEGS lacked a detectable pathogenic SCARF2 variant, genetic heterogeneity is likely. Our study shows the importance of performing genetic testing on individuals with the VDEGS "phenotype," either as a targeted gene analysis (SCARF2, ABL1) or WES/WGS. Additionally, individuals with the combination of arachnodactyly and blepharophimosis should undergo echocardiography while awaiting results of molecular testing due to the overlapping physical features of VDEGS and CHDSKM. [ABSTRACT FROM AUTHOR]

Published
2021
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17. Paralog Studies Augment Gene Discovery: DDX and DHX Genes

Author

Paine, Ingrid, primary, Posey, Jennifer E., additional, Grochowski, Christopher M., additional, Jhangiani, Shalini N., additional, Rosenheck, Sarah, additional, Kleyner, Robert, additional, Marmorale, Taylor, additional, Yoon, Margaret, additional, Wang, Kai, additional, Robison, Reid, additional, Cappuccio, Gerarda, additional, Pinelli, Michele, additional, Magli, Adriano, additional, Coban Akdemir, Zeynep, additional, Hui, Joannie, additional, Yeung, Wai Lan, additional, Wong, Bibiana K.Y., additional, Ortega, Lucia, additional, Bekheirnia, Mir Reza, additional, Bierhals, Tatjana, additional, Hempel, Maja, additional, Johannsen, Jessika, additional, Santer, René, additional, Aktas, Dilek, additional, Alikasifoglu, Mehmet, additional, Bozdogan, Sevcan, additional, Aydin, Hatip, additional, Karaca, Ender, additional, Bayram, Yavuz, additional, Ityel, Hadas, additional, Dorschner, Michael, additional, White, Janson J., additional, Wilichowski, Ekkehard, additional, Wortmann, Saskia B., additional, Casella, Erasmo B., additional, Kitajima, Joao Paulo, additional, Kok, Fernando, additional, Monteiro, Fabiola, additional, Muzny, Donna M., additional, Bamshad, Michael, additional, Gibbs, Richard A., additional, Sutton, V. Reid, additional, Van Esch, Hilde, additional, Brunetti-Pierri, Nicola, additional, Hildebrandt, Friedhelm, additional, Brautbar, Ariel, additional, Van den Veyver, Ignatia B., additional, Glass, Ian, additional, Lessel, Davor, additional, Lyon, Gholson J., additional, and Lupski, James R., additional

Published
2019
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18. Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease

Author

Jolly, Angad, primary, Bayram, Yavuz, additional, Turan, Serap, additional, Aycan, Zehra, additional, Tos, Tulay, additional, Abali, Zehra Yavas, additional, Hacihamdioglu, Bulent, additional, Coban Akdemir, Zeynep Hande, additional, Hijazi, Hadia, additional, Bas, Serpil, additional, Atay, Zeynep, additional, Guran, Tulay, additional, Abali, Saygin, additional, Bas, Firdevs, additional, Darendeliler, Feyza, additional, Colombo, Roberto, additional, Barakat, Tahsin Stefan, additional, Rinne, Tuula, additional, White, Janson J, additional, Yesil, Gozde, additional, Gezdirici, Alper, additional, Gulec, Elif Yilmaz, additional, Karaca, Ender, additional, Pehlivan, Davut, additional, Jhangiani, Shalini N, additional, Muzny, Donna M, additional, Poyrazoglu, Sukran, additional, Bereket, Abdullah, additional, Gibbs, Richard A, additional, Posey, Jennifer E, additional, and Lupski, James R, additional

Published
2019
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19. Exome sequencing of family trios from the National Birth Defects Prevention Study: Tapping into a rich resource of genetic and environmental data.

Author

Jenkins, Mary M., Almli, Lynn M., Pangilinan, Faith, Chong, Jessica X., Blue, Elizabeth E., Shapira, Stuart K., White, Janson, McGoldrick, Daniel, Smith, Joshua D., Mullikin, James C., Bean, Christopher J., Nembhard, Wendy N., Lou, Xiang‐Yang, Shaw, Gary M., Romitti, Paul A., Keppler‐Noreuil, Kim, Yazdy, Mahsa M., Kay, Denise M., Carter, Tonia C., and Olshan, Andrew F.

Abstract

Background: The National Birth Defects Prevention Study (NBDPS) is a multisite, population‐based, case–control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens. Methods: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA. Results: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol. Conclusions: This proof‐of‐principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well‐characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene–environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers. [ABSTRACT FROM AUTHOR]

Published
2019
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20. Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles

Author

Coban-Akdemir, Zeynep, primary, White, Janson J., additional, Song, Xiaofei, additional, Jhangiani, Shalini N., additional, Fatih, Jawid M., additional, Gambin, Tomasz, additional, Bayram, Yavuz, additional, Chinn, Ivan K., additional, Karaca, Ender, additional, Punetha, Jaya, additional, Poli, Cecilia, additional, Boerwinkle, Eric, additional, Shaw, Chad A., additional, Orange, Jordan S., additional, Gibbs, Richard A., additional, Lappalainen, Tuuli, additional, Lupski, James R., additional, and Carvalho, Claudia M.B., additional

Published
2018
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21. WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome

Author

White, Janson J., primary, Mazzeu, Juliana F., additional, Coban-Akdemir, Zeynep, additional, Bayram, Yavuz, additional, Bahrambeigi, Vahid, additional, Hoischen, Alexander, additional, van Bon, Bregje W.M., additional, Gezdirici, Alper, additional, Gulec, Elif Yilmaz, additional, Ramond, Francis, additional, Touraine, Renaud, additional, Thevenon, Julien, additional, Shinawi, Marwan, additional, Beaver, Erin, additional, Heeley, Jennifer, additional, Hoover-Fong, Julie, additional, Durmaz, Ceren D., additional, Karabulut, Halil Gurhan, additional, Marzioglu-Ozdemir, Ebru, additional, Cayir, Atilla, additional, Duz, Mehmet B., additional, Seven, Mehmet, additional, Price, Susan, additional, Ferreira, Barbara Merfort, additional, Vianna-Morgante, Angela M., additional, Ellard, Sian, additional, Parrish, Andrew, additional, Stals, Karen, additional, Flores-Daboub, Josue, additional, Jhangiani, Shalini N., additional, Gibbs, Richard A., additional, Brunner, Han G., additional, Sutton, V. Reid, additional, Lupski, James R., additional, and Carvalho, Claudia M.B., additional

Published
2018
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23. REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis

Author

Bayram, Yavuz, primary, White, Janson J., additional, Elcioglu, Nursel, additional, Cho, Megan T., additional, Zadeh, Neda, additional, Gedikbasi, Asuman, additional, Palanduz, Sukru, additional, Ozturk, Sukru, additional, Cefle, Kivanc, additional, Kasapcopur, Ozgur, additional, Coban Akdemir, Zeynep, additional, Pehlivan, Davut, additional, Begtrup, Amber, additional, Carvalho, Claudia M.B., additional, Paine, Ingrid Sophie, additional, Mentes, Ali, additional, Bektas-Kayhan, Kivanc, additional, Karaca, Ender, additional, Jhangiani, Shalini N., additional, Muzny, Donna M., additional, Gibbs, Richard A., additional, and Lupski, James R., additional

Published
2017
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24. Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics

Author

Loviglio, Maria Nicla, primary, Beck, Christine R., additional, White, Janson J., additional, Leleu, Marion, additional, Harel, Tamar, additional, Guex, Nicolas, additional, Niknejad, Anne, additional, Bi, Weimin, additional, Chen, Edward S., additional, Crespo, Isaac, additional, Yan, Jiong, additional, Charng, Wu-Lin, additional, Gu, Shen, additional, Fang, Ping, additional, Coban-Akdemir, Zeynep, additional, Shaw, Chad A., additional, Jhangiani, Shalini N., additional, Muzny, Donna M., additional, Gibbs, Richard A., additional, Rougemont, Jacques, additional, Xenarios, Ioannis, additional, Lupski, James R., additional, and Reymond, Alexandre, additional

Published
2016
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25. De novo and inherited variants in ZNF292underlie a neurodevelopmental disorder with features of autism spectrum disorder

Author

Mirzaa, Ghayda M., Chong, Jessica X., Piton, Amélie, Popp, Bernt, Foss, Kimberly, Guo, Hui, Harripaul, Ricardo, Xia, Kun, Scheck, Joshua, Aldinger, Kimberly A., Sajan, Samin A., Tang, Sha, Bonneau, Dominique, Beck, Anita, White, Janson, Mahida, Sonal, Harris, Jacqueline, Smith-Hicks, Constance, Hoyer, Juliane, Zweier, Christiane, Reis, André, Thiel, Christian T., Jamra, Rami Abou, Zeid, Natasha, Yang, Amy, Farach, Laura S., Walsh, Laurence, Payne, Katelyn, Rohena, Luis, Velinov, Milen, Ziegler, Alban, Schaefer, Elise, Gatinois, Vincent, Geneviève, David, Simon, Marleen E.H., Kohler, Jennefer, Rotenberg, Joshua, Wheeler, Patricia, Larson, Austin, Ernst, Michelle E., Akman, Cigdem I., Westman, Rachel, Blanchet, Patricia, Schillaci, Lori-Anne, Vincent-Delorme, Catherine, Gripp, Karen W., Mattioli, Francesca, Guyader, Gwenaël Le, Gerard, Bénédicte, Mathieu-Dramard, Michèle, Morin, Gilles, Sasanfar, Roksana, Ayub, Muhammad, Vasli, Nasim, Yang, Sandra, Person, Rick, Monaghan, Kristin G., Nickerson, Deborah A., van Binsbergen, Ellen, Enns, Gregory M., Dries, Annika M., Rowe, Leah J., Tsai, Anne C.H., Svihovec, Shayna, Friedman, Jennifer, Agha, Zehra, Qamar, Raheel, Rodan, Lance H., Martinez-Agosto, Julian, Ockeloen, Charlotte W., Vincent, Marie, Sunderland, William James, Bernstein, Jonathan A., Eichler, Evan E., Vincent, John B., and Bamshad, Michael J.

Abstract

Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).

Published
2020
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26. POGZ truncating alleles cause syndromic intellectual disability

Author

White, Janson, primary, Beck, Christine R., additional, Harel, Tamar, additional, Posey, Jennifer E., additional, Jhangiani, Shalini N., additional, Tang, Sha, additional, Farwell, Kelly D., additional, Powis, Zöe, additional, Mendelsohn, Nancy J., additional, Baker, Janice A., additional, Pollack, Lynda, additional, Mason, Kati J., additional, Wierenga, Klaas J., additional, Arrington, Daniel K., additional, Hall, Melissa, additional, Psychogios, Apostolos, additional, Fairbrother, Laura, additional, Walkiewicz, Magdalena, additional, Person, Richard E., additional, Niu, Zhiyv, additional, Zhang, Jing, additional, Rosenfeld, Jill A., additional, Muzny, Donna M., additional, Eng, Christine, additional, Beaudet, Arthur L., additional, Lupski, James R., additional, Boerwinkle, Eric, additional, Gibbs, Richard A., additional, Yang, Yaping, additional, Xia, Fan, additional, and Sutton, V. Reid, additional

Published
2016
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27. Hutterite‐type cataract maps to chromosome 6p21.32‐p21.31, cosegregates with a homozygous mutation inLEMD2, and is associated with sudden cardiac death

Author

Boone, Philip M., primary, Yuan, Bo, additional, Gu, Shen, additional, Ma, Zhiwei, additional, Gambin, Tomasz, additional, Gonzaga‐Jauregui, Claudia, additional, Jain, Mahim, additional, Murdock, Todd J., additional, White, Janson J., additional, Jhangiani, Shalini N., additional, Walker, Kimberly, additional, Wang, Qiaoyan, additional, Muzny, Donna M., additional, Gibbs, Richard A., additional, Hejtmancik, J. Fielding, additional, Lupski, James R., additional, Posey, Jennifer E., additional, and Lewis, Richard A., additional

Published
2015
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28. DVL1 Frameshift Mutations Clustering in the Penultimate Exon Cause Autosomal-Dominant Robinow Syndrome

Author

White, Janson, primary, Mazzeu, Juliana F., additional, Hoischen, Alexander, additional, Jhangiani, Shalini N., additional, Gambin, Tomasz, additional, Alcino, Michele Calijorne, additional, Penney, Samantha, additional, Saraiva, Jorge M., additional, Hove, Hanne, additional, Skovby, Flemming, additional, Kayserili, Hülya, additional, Estrella, Elicia, additional, Vulto-van Silfhout, Anneke T., additional, Steehouwer, Marloes, additional, Muzny, Donna M., additional, Sutton, V. Reid, additional, Gibbs, Richard A., additional, Lupski, James R., additional, Brunner, Han G., additional, van Bon, Bregje W.M., additional, and Carvalho, Claudia M.B., additional

Published
2015
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29. Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death.

Author

Boone, Philip M., Yuan, Bo, Gu, Shen, Ma, Zhiwei, Gambin, Tomasz, Gonzaga‐Jauregui, Claudia, Jain, Mahim, Murdock, Todd J., White, Janson J., Jhangiani, Shalini N., Walker, Kimberly, Wang, Qiaoyan, Muzny, Donna M., Gibbs, Richard A., Hejtmancik, J. Fielding, Lupski, James R., Posey, Jennifer E., and Lewis, Richard A.

Subjects
CATARACT, CATARACT in children, EXOMES, MISSENSE mutation, POINT mutation (Biology), GENETICS
Abstract

Background Juvenile-onset cataracts are known among the Hutterites of North America. Despite being identified over 30 years ago, this autosomal recessive condition has not been mapped, and the disease gene is unknown. Methods We performed whole exome sequencing of three Hutterite-type cataract trios and follow-up genotyping and mapping in four extended kindreds. Results Trio exomes enabled genome-wide autozygosity mapping, which localized the disease gene to a 9.5-Mb region on chromosome 6p. This region contained two candidate variants, LEMD2 c.T38G and MUC21 c.665delC. Extended pedigrees recruited for variant genotyping revealed multiple additional relatives with juvenile-onset cataract, as well as six deceased relatives with both cataracts and sudden cardiac death. The candidate variants were genotyped in 84 family members, including 17 with cataracts; only the variant in LEMD2 cosegregated with cataracts ( LOD = 9.62). SNP-based fine mapping within the 9.5 Mb linked region supported this finding by refining the cataract locus to a 0.5- to 2.9-Mb subregion (6p21.32-p21.31) containing LEMD2 but not MUC21. LEMD2 is expressed in mouse and human lenses and encodes a LEM domain-containing protein; the c.T38G missense mutation is predicted to mutate a highly conserved residue within this domain (p.Leu13Arg). Conclusion We performed a genetic and genomic study of Hutterite-type cataract and found evidence for an association of this phenotype with sudden cardiac death. Using combined genetic and genomic approaches, we mapped cataracts to a small portion of chromosome 6 and propose that they result from a homozygous missense mutation in LEMD2. [ABSTRACT FROM AUTHOR]

Published
2016
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30. Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics

Author

Loviglio, Maria Nicla, Beck, Christine R., White, Janson J., Leleu, Marion, Harel, Tamar, Guex, Nicolas, Niknejad, Anne, Bi, Weimin, Chen, Edward S., Crespo, Isaac, Yan, Jiong, Charng, Wu-Lin, Gu, Shen, Fang, Ping, Coban-Akdemir, Zeynep, Shaw, Chad A., Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Rougemont, Jacques, Xenarios, Ioannis, Lupski, James R., and Reymond, Alexandre

Subjects
Male, Text mining, lcsh:QH426-470, Intellectual disability, lcsh:Medicine, Real-Time Polymerase Chain Reaction, Disease network, Mice, Genetics, Animals, Humans, Exome, Gene Regulatory Networks, Chromatin conformation, Diagnostic, Genetics(clinical), RNA, Messenger, Molecular Biology, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Research, lcsh:R, Genomics, Embryo, Mammalian, Mice, Inbred C57BL, lcsh:Genetics, Phenotype, Mutation, Trans-Activators, Molecular Medicine, Female, Smith-Magenis Syndrome, Transcriptome, Transcription Factors
Abstract

Background Smith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances, and stereotypic behaviors. Methods We investigated a cohort of 15 individuals with a clinical suspicion of SMS who showed neither deletion in the SMS critical region nor damaging variants in RAI1 using whole exome sequencing. A combination of network analysis (co-expression and biomedical text mining), transcriptomics, and circularized chromatin conformation capture (4C-seq) was applied to verify whether modified genes are part of the same disease network as known SMS-causing genes. Results Potentially deleterious variants were identified in nine of these individuals using whole-exome sequencing. Eight of these changes affect KMT2D, ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C, and POGZ, known to be associated with Kabuki syndrome 1, Mowat-Wilson syndrome, cardiofaciocutaneous syndrome, glycine encephalopathy, mental retardation and microcephaly with pontine and cerebellar hypoplasia, X-linked mental retardation 13, X-linked mental retardation Claes-Jensen type, and White-Sutton syndrome, respectively. The ninth individual carries a de novo variant in JAKMIP1, a regulator of neuronal translation that was recently found deleted in a patient with autism spectrum disorder. Analyses of co-expression and biomedical text mining suggest that these pathologies and SMS are part of the same disease network. Further support for this hypothesis was obtained from transcriptome profiling that showed that the expression levels of both Zeb2 and Map2k2 are perturbed in Rai1 –/– mice. As an orthogonal approach to potentially contributory disease gene variants, we used chromatin conformation capture to reveal chromatin contacts between RAI1 and the loci flanking ZEB2 and GLDC, as well as between RAI1 and human orthologs of the genes that show perturbed expression in our Rai1 –/– mouse model. Conclusions These holistic studies of RAI1 and its interactions allow insights into SMS and other disorders associated with intellectual disability and behavioral abnormalities. Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0359-z) contains supplementary material, which is available to authorized users.

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31. Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease

Author

Serap Turan, Zeynep Coban Akdemir, Angad Jolly, Firdevs Bas, Davut Pehlivan, Hadia Hijazi, Zehra Yavas Abali, Tuula Rinne, Jennifer E. Posey, Yavuz Bayram, Tahsin Stefan Barakat, Tulay Tos, Roberto Colombo, Shalini N. Jhangiani, Gozde Yesil, Sukran Poyrazoglu, Zeynep Atay, Alper Gezdirici, James R. Lupski, Donna M. Muzny, Tulay Guran, Zehra Aycan, Richard A. Gibbs, Elif Yilmaz Gulec, Janson White, Serpil Bas, Ender Karaca, Feyza Darendeliler, Abdullah Bereket, Bülent Hacıhamdioğlu, Saygin Abali, İstinye Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Bülent Hacıhamdioğlu / 0000-0001-7070-6429, Hacihamdioglu, Bulent, Bülent Hacıhamdioğlu / GBK-6773-2022, Bülent Hacıhamdioğlu / 22134579900, Clinical Genetics, YEŞİL, Gözde, Jolly, Angad, Bayram, Yavuz, Turan, Serap, Aycan, Zehra, Tos, Tulay, Abali, Zehra Yavas, Akdemir, Zeynep Hande Coban, Hijazi, Hadia, Bas, Serpil, Atay, Zeynep, Guran, Tulay, Abali, Saygin, Bas, Firdevs, Darendeliler, Feyza, Colombo, Roberto, Barakat, Tahsin Stefan, Rinne, Tuula, White, Janson J., Yesil, Gozde, Gezdirici, Alper, Gulec, Elif Yilmaz, Karaca, Ender, Pehlivan, Davut, Jhangiani, Shalini N., Muzny, Donna M., Poyrazoglu, Sukran, Bereket, Abdullah, Gibbs, Richard A., Posey, Jennifer E., and Lupski, James R.

Subjects
MECHANISM, 0301 basic medicine, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, PROTEIN, Cell Cycle Proteins, Disease, Primary Ovarian Insufficiency, VARIANTS, Biochemistry, Cohort Studies, 0302 clinical medicine, Endocrinology, Gene Frequency, Locus heterogeneity, FAILURE, Exome sequencing, Jolly A., Bayram Y., Turan S., Aycan Z., Tos T., Abali Z. Y. , Hacihamdioglu B., Akdemir Z. H. C. , Hijazi H., Bas S., et al., -Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease-, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, cilt.104, ss.3049-3067, 2019, Genetics, 030219 obstetrics & reproductive medicine, Minichromosome Maintenance Proteins, REARRANGEMENTS, Oligogenic Inheritance, DNA-Binding Proteins, INSIGHTS, Female, medicine.medical_specialty, Immunoglobulins, Locus (genetics), Genomics, Biology, 03 medical and health sciences, Hypergonadotropic hypogonadism, All institutes and research themes of the Radboud University Medical Center, Internal medicine, Exome Sequencing, medicine, Humans, HOP2-MND1, Settore BIO/10 - BIOCHIMICA, Allele frequency, Clinical Research Articles, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, MUTATIONS, Hypogonadism, Biochemistry (medical), DNA Helicases, medicine.disease, GENE, 030104 developmental biology, exome
Abstract

Context: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hyper-gonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait. Objective: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI. Design, Setting, and Participants: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity. Results: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds. Conclusions: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI. National Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); National Heart Lung and Blood Institute (NHBLI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [UM1 HG006542]; National Institute of Neurologic Disorders and Stroke (NINDS)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R35NS105078]; NHGRIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08 HG008986, U54HG003273]; Howard Hughes Medical Research Fellows Program; Baylor College of Medicine Medical Scientist Training Program; Clinical Research Training Scholarship in Neuromuscular Disease; American Academy of Neurology (AAN); American Brain Foundation (ABF); Netherlands Organization for Scientific Research (ZonMW Veni)Netherlands Organization for Scientific Research (NWO) [91617021]; NARSAD Young Investigator Grant from the Brain & Behavior Research FoundationNARSAD; Muscle Study Group (MSG) This study was supported in part by the National Human Genome Research Institute (NHGRI) and National Heart Lung and Blood Institute (NHBLI) to the Baylor-Hopkins Center for Mendelian Genomics (BHCMG; UM1 HG006542 to J.R.L.); NHGRI grant to Baylor College of Medicine Human Genome Sequencing Center (U54HG003273 to R.A.G.), and National Institute of Neurologic Disorders and Stroke (NINDS; R35NS105078 to J.R.L.). J.E.P. was supported by NHGRI K08 HG008986. A.J. was supported in part by the Howard Hughes Medical Research Fellows Program and the Baylor College of Medicine Medical Scientist Training Program. D. P. is supported by Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Academy of Neurology (AAN), American Brain Foundation (ABF), and Muscle Study Group (MSG). T.S.B. was supported by the Netherlands Organization for Scientific Research (ZonMW Veni, Grant 91617021) and by an NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. WOS:000482558500001 31042289 Q1

Published
2019

32. REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis

Author

Janson White, Megan T. Cho, James R. Lupski, Kivanc Cefle, Claudia M.B. Carvalho, Donna M. Muzny, Kivanc Bektas-Kayhan, Yavuz Bayram, Ender Karaca, Nursel Elcioglu, Richard A. Gibbs, Shalini N. Jhangiani, Amber Begtrup, Ali Menteş, Neda Zadeh, Zeynep Coban Akdemir, Sukru Ozturk, Ozgur Kasapcopur, Ingrid S. Paine, Asuman Gedikbasi, Davut Pehlivan, Sukru Palanduz, Bayram, Yavuz, White, Janson J., Elcioglu, Nursel, Cho, Megan T., Zadeh, Neda, Gedikbasi, Asuman, Palanduz, Sukru, Ozturk, Sukru, Cefle, Kivanc, Kasapcopur, Ozgur, Akdemir, Zeynep Coban, Pehlivan, Davut, Begtrup, Amber, Carvalho, Claudia M. B., Paine, Ingrid Sophie, Mentes, Ali, Bektas-Kayhan, Kivanc, Karaca, Ender, Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., and Lupski, James R.

Subjects
0301 basic medicine, Male, NEUROENDOCRINE DIFFERENTIATION, FIBROBLASTS, Adolescent, PROTEIN, RE1-silencing transcription factor, Biology, medicine.disease_cause, Germline, 03 medical and health sciences, Exon, 0302 clinical medicine, TUMOR, Report, Chromosome Segregation, Genetics, medicine, Humans, Family, Genetic Predisposition to Disease, Genetics (clinical), Exome sequencing, GENE-EXPRESSION, Fibromatosis, Gingival, Mutation, Autosome, Base Sequence, Genetic heterogeneity, REPRESSOR, 030206 dentistry, TRANSCRIPTION FACTOR REST, Exons, Middle Aged, medicine.disease, CANCER, Hereditary gingival fibromatosis, Pedigree, Repressor Proteins, 030104 developmental biology, biology.protein, Female, SIGNALING PATHWAY, RESTRICTIVE SILENCER FACTOR
Abstract

Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3–p22.3, 5q13–q22, and 11p15) have been mapped to autosomes and one gene ( SOS1 ) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor ( REST ) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype.

Published
2017

33. Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.

Author

Zhang C, Jolly A, Shayota BJ, Mazzeu JF, Du H, Dawood M, Soper PC, Ramalho de Lima A, Ferreira BM, Coban-Akdemir Z, White J, Shears D, Thomson FR, Douglas SL, Wainwright A, Bailey K, Wordsworth P, Oldridge M, Lester T, Calder AD, Dumic K, Banka S, Donnai D, Jhangiani SN, Potocki L, Chung WK, Mora S, Northrup H, Ashfaq M, Rosenfeld JA, Mason K, Pollack LC, McConkie-Rosell A, Kelly W, McDonald M, Hauser NS, Leahy P, Powell CM, Boy R, Honjo RS, Kok F, Martelli LR, Filho VO, Genomics England Research Consortium, Muzny DM, Gibbs RA, Posey JE, Liu P, Lupski JR, Sutton VR, and Carvalho CMB

Abstract

Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated ( DVL1 , DVL3 , FZD2 , NXN , ROR2 , and WNT5A ). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2 . We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1 , DVL2 , and DVL3 variants, demonstrating no phenotypic distinction between the NXN -autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A , FZD2 , and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins., Competing Interests: BCM and Miraca Holdings have formed a joint venture with shared ownership and governance of BG, which performs clinical microarray analysis (CMA), clinical ES (cES), and clinical biochemical studies. V.R.S. and P.L. receive professional services compensation from BG and J.R.L. serves on the Scientific Advisory Board of the BG. J.R.L. has stock ownership in 23andMe, is a paid consultant for the Regeneron Genetics Center, and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. W.K.C. is a is a paid consultant for the Regeneron Genetics Center. P.C.S. and S.M. are employees of GeneDx. The other authors declare no competing interests., (© 2021 The Author(s).)

Published
2021
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34. Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death.

Author

Boone PM, Yuan B, Gu S, Ma Z, Gambin T, Gonzaga-Jauregui C, Jain M, Murdock TJ, White JJ, Jhangiani SN, Walker K, Wang Q, Muzny DM, Gibbs RA, Hejtmancik JF, Lupski JR, Posey JE, and Lewis RA

Abstract

Background: Juvenile-onset cataracts are known among the Hutterites of North America. Despite being identified over 30 years ago, this autosomal recessive condition has not been mapped, and the disease gene is unknown., Methods: We performed whole exome sequencing of three Hutterite-type cataract trios and follow-up genotyping and mapping in four extended kindreds., Results: Trio exomes enabled genome-wide autozygosity mapping, which localized the disease gene to a 9.5-Mb region on chromosome 6p. This region contained two candidate variants, LEMD2 c.T38G and MUC21 c.665delC. Extended pedigrees recruited for variant genotyping revealed multiple additional relatives with juvenile-onset cataract, as well as six deceased relatives with both cataracts and sudden cardiac death. The candidate variants were genotyped in 84 family members, including 17 with cataracts; only the variant in LEMD2 cosegregated with cataracts (LOD = 9.62). SNP-based fine mapping within the 9.5 Mb linked region supported this finding by refining the cataract locus to a 0.5- to 2.9-Mb subregion (6p21.32-p21.31) containing LEMD2 but not MUC21. LEMD2 is expressed in mouse and human lenses and encodes a LEM domain-containing protein; the c.T38G missense mutation is predicted to mutate a highly conserved residue within this domain (p.Leu13Arg)., Conclusion: We performed a genetic and genomic study of Hutterite-type cataract and found evidence for an association of this phenotype with sudden cardiac death. Using combined genetic and genomic approaches, we mapped cataracts to a small portion of chromosome 6 and propose that they result from a homozygous missense mutation in LEMD2.

Published
2015
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35. White-Sutton Syndrome

Author

Assia Batzir N, White J, Sutton VR, Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, and Amemiya A

Abstract

Clinical Characteristics: White-Sutton syndrome is a neurodevelopmental disorder characterized by a wide spectrum of cognitive dysfunction, developmental delays (particularly in speech and language acquisition), hypotonia, autism spectrum disorder, and other behavioral problems. Additional features commonly reported include seizures, refractive errors and strabismus, hearing loss, sleep disturbance (particularly sleep apnea), feeding and gastrointestinal problems, mild genital abnormalities in males, and urinary tract involvement in both males and females., Diagnosis/testing: The diagnosis of White-Sutton syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in POGZ identified by molecular genetic testing., Management: Treatment of manifestations: Developmental delay/intellectual disability, speech and language acquisition, behavioral issues, seizures, refractive errors and strabismus, hearing impairment, sleep disturbance, feeding and gastrointestinal issues, and genitourinary problems are managed by specialists per standard care. Surveillance: Follow up of the common manifestations at each clinic visit., Genetic Counseling: White-Sutton syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Most probands reported to date whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant. Rarely, individuals with White-Sutton syndrome have the disorder as the result of a POGZ pathogenic variant. Rarely, individuals with White-Sutton syndrome have the disorder as the result of a POGZ pathogenic variant inherited from a heterozygous parent with features such as developmental delay and/or mild intellectual disability. Once the POGZ pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible., (Copyright © 1993-2022, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.)

Published
1993

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