Search

Your search keyword '"Hiatt, Susan"' showing total 212 results
Start Over Author "Hiatt, Susan"
212 results on '"Hiatt, Susan"'

1. MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway

Author

Gong, Maolei, Li, Jiayi, Qin, Zailong, Machado Bressan Wilke, Matheus Vernet, Liu, Yijun, Li, Qian, Liu, Haoran, Liang, Chen, Morales-Rosado, Joel A., Cohen, Ana S.A., Hughes, Susan S., Sullivan, Bonnie R., Waddell, Valerie, van den Boogaard, Marie-José H., van Jaarsveld, Richard H., van Binsbergen, Ellen, van Gassen, Koen L., Wang, Tianyun, Hiatt, Susan M., Amaral, Michelle D., Kelley, Whitley V., Zhao, Jianbo, Feng, Weixing, Ren, Changhong, Yu, Yazhen, Boczek, Nicole J., Ferber, Matthew J., Lahner, Carrie, Elliott, Sherr, Ruan, Yiyan, Mignot, Cyril, Keren, Boris, Xie, Hua, Wang, Xiaoyan, Popp, Bernt, Zweier, Christiane, Piard, Juliette, Coubes, Christine, Mau-Them, Frederic Tran, Safraou, Hana, Innes, A. Micheil, Gauthier, Julie, Michaud, Jacques L., Koboldt, Daniel C., Sylvie, Odent, Willems, Marjolaine, Tan, Wen-Hann, Cogne, Benjamin, Rieubland, Claudine, Braun, Dominique, McLean, Scott Douglas, Platzer, Konrad, Zacher, Pia, Oppermann, Henry, Evenepoel, Lucie, Blanc, Pierre, El Khattabi, Laïla, Haque, Neshatul, Dsouza, Nikita R., Zimmermann, Michael T., Urrutia, Raul, Klee, Eric W., Shen, Yiping, Du, Hongzhen, Rappaport, Leonard, Liu, Chang-Mei, and Chen, Xiaoli

Published
2024
Full Text
View/download PDF

2. Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder

Author

Pavinato, Lisa, Stanic, Jennifer, Barzasi, Marta, Gurgone, Antonia, Chiantia, Giuseppe, Cipriani, Valentina, Eberini, Ivano, Palazzolo, Luca, Di Luca, Monica, Costa, Alex, Marcantoni, Andrea, Biamino, Elisa, Spada, Marco, Hiatt, Susan M., Kelley, Whitley V., Vestito, Letizia, Sisodiya, Sanjay M., Efthymiou, Stephanie, Chand, Prem, Kaiyrzhanov, Rauan, Bruselles, Alessandro, Cardaropoli, Simona, Tartaglia, Marco, De Rubeis, Silvia, Buxbaum, Joseph D., Smedley, Damian, Ferrero, Giovanni Battista, Giustetto, Maurizio, Gardoni, Fabrizio, and Brusco, Alfredo

Published
2023
Full Text
View/download PDF

3. Poison exon annotations improve the yield of clinically relevant variants in genomic diagnostic testing

Author

Felker, Stephanie A., Lawlor, James M.J., Hiatt, Susan M., Thompson, Michelle L., Latner, Donald R., Finnila, Candice R., Bowling, Kevin M., Bonnstetter, Zachary T., Bonini, Katherine E., Kelly, Nicole R., Kelley, Whitley V., Hurst, Anna C.E., Rashid, Salman, Kelly, Melissa A., Nakouzi, Ghunwa, Hendon, Laura G., Bebin, E. Martina, Kenny, Eimear E., and Cooper, Gregory M.

Published
2023
Full Text
View/download PDF

4. Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size (vol 142, pg 2617, 2019)

Author

Le Duc, Diana, Giulivi, Cecilia, Hiatt, Susan M, Napoli, Eleonora, Panoutsopoulos, Alexios, De Crescenzo, Angelo Harlan, Kotzaeridou, Urania, Syrbe, Steffen, Anagnostou, Evdokia, Azage, Meron, Bend, Renee, Begtrup, Amber, Brown, Natasha J, Buttner, Benjamin, Cho, Megan T, Cooper, Gregory M, Doering, Jan H, Dubourg, Christele, Everman, David B, Hildebrand, Michael S, Santos, Francis Jeshira Reynoso, Kellam, Barbara, Keller-Ramey, Jennifer, Lemke, Johannes R, Liu, Shuxi, Niyazov, Dmitriy, Payne, Katelyn, Person, Richard, Quelin, Chloe, Schnur, Rhonda E, Smith, Brooke T, Strober, Jonathan, Walker, Susan, Wallis, Mathew, Walsh, Laurence, Yang, Sandra, Yuen, Ryan KC, Ziegler, Andreas, Sticht, Heinrich, Pride, Michael C, Orosco, Lori, Martinez-Cerdeno, Veronica, Silverman, Jill L, Crawley, Jacqueline N, Scherer, Stephen W, Zarbalis, Konstantinos S, and Jamra, Rami

Subjects
Neurology & Neurosurgery, Medical and Health Sciences, Psychology and Cognitive Sciences
Published
2019

5. Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size

Author

Le Duc, Diana, Giulivi, Cecilia, Hiatt, Susan M, Napoli, Eleonora, Panoutsopoulos, Alexios, De Crescenzo, Angelo Harlan, Kotzaeridou, Urania, Syrbe, Steffen, Anagnostou, Evdokia, Azage, Meron, Bend, Renee, Begtrup, Amber, Brown, Natasha J, Büttner, Benjamin, Cho, Megan T, Cooper, Gregory M, Doering, Jan H, Dubourg, Christèle, Everman, David B, Hildebrand, Michael S, Santos, Francis Jeshira Reynoso, Kellam, Barbara, Keller-Ramey, Jennifer, Lemke, Johannes R, Liu, Shuxi, Niyazov, Dmitriy, Payne, Katelyn, Person, Richard, Quélin, Chloé, Schnur, Rhonda E, Smith, Brooke T, Strober, Jonathan, Walker, Susan, Wallis, Mathew, Walsh, Laurence, Yang, Sandra, Yuen, Ryan KC, Ziegler, Andreas, Sticht, Heinrich, Pride, Michael C, Orosco, Lori, Martínez-Cerdeño, Verónica, Silverman, Jill L, Crawley, Jacqueline N, Scherer, Stephen W, Zarbalis, Konstantinos S, and Jamra, Rami

Subjects
Biomedical and Clinical Sciences, Health Sciences, Psychology, Stem Cell Research, Neurosciences, Mental Health, Biotechnology, Brain Disorders, Genetics, Intellectual and Developmental Disabilities (IDD), Clinical Research, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Neurological, Mental health, Adaptor Proteins, Signal Transducing, Adolescent, Animals, Autophagy-Related Proteins, Brain, Child, Child, Preschool, Female, Genetic Variation, Humans, Male, Mice, Mice, Transgenic, Neurodevelopmental Disorders, Organ Size, Protein Structure, Secondary, WDFY3, brain size, neurodevelopmental delay, intellectual disability, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Abstract

The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.

Published
2019

6. Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations

Author

Tripathy, Ratna, Leca, Ines, van Dijk, Tessa, Weiss, Janneke, van Bon, Bregje W, Sergaki, Maria Christina, Gstrein, Thomas, Breuss, Martin, Tian, Guoling, Bahi-Buisson, Nadia, Paciorkowski, Alexander R, Pagnamenta, Alistair T, Wenninger-Weinzierl, Andrea, Martinez-Reza, Maria Fernanda, Landler, Lukas, Lise, Stefano, Taylor, Jenny C, Terrone, Gaetano, Vitiello, Giuseppina, Del Giudice, Ennio, Brunetti-Pierri, Nicola, D’Amico, Alessandra, Reymond, Alexandre, Voisin, Norine, Bernstein, Jonathan A, Farrelly, Ellyn, Kini, Usha, Leonard, Thomas A, Valence, Stéphanie, Burglen, Lydie, Armstrong, Linlea, Hiatt, Susan M, Cooper, Gregory M, Aldinger, Kimberly A, Dobyns, William B, Mirzaa, Ghayda, Pierson, Tyler Mark, Baas, Frank, Chelly, Jamel, Cowan, Nicholas J, and Keays, David Anthony

Subjects
Biomedical and Clinical Sciences, Neurosciences, Rare Diseases, Pediatric, Genetics, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Congenital Structural Anomalies, 2.1 Biological and endogenous factors, Aetiology, Neurological, Agenesis of Corpus Callosum, Animals, Animals, Newborn, Apoptosis, Brain, Cells, Cultured, Cerebellum, Child, Developmental Disabilities, Disease Models, Animal, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Humans, Male, Malformations of Cortical Development, Mice, Mice, Inbred C57BL, Mice, Knockout, Microtubule-Associated Proteins, Mutation, Nerve Tissue Proteins, Nervous System Malformations, PAX6 Transcription Factor, MAST1, cerebellar hypoplasia, corpus callosum, microdeletion, microtubules, Psychology, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.

Published
2018

7. MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway

Author

Gong, Maolei, primary, Li, Jiayi, additional, Liu, Yijun, additional, Matheus, Vernet Machado Bressan Wilk, additional, Li, Qian, additional, Liu, Haoran, additional, Liang, Chen, additional, Joel A, Morales-Rosado, additional, Cohen, Ana S.A., additional, Hughes, Susan S., additional, Sullivan, Bonnie R, additional, Waddell, Valerie, additional, Henriette van den Boogaard, Marie Jose, additional, van Jaarsveld, Richard H., additional, Binsbergen, Ellen van, additional, van Gassen, Koen L, additional, Wang, Tianyun, additional, Hiatt, Susan M., additional, Amaral, Michelle D., additional, Kelley, Whitley V., additional, Zhao, Jianbo, additional, Feng, Weixing, additional, Ren, Changhong, additional, Yu, Yazhen, additional, Boczek, Nicole J, additional, Ferber, Matthew J., additional, Lahner, Carrie, additional, Elliott, Sherr, additional, Ruan, Yiyan, additional, Mignot, Cyril, additional, Keren, Boris, additional, Xie, Hua, additional, Wang, Xiaoyan, additional, Popp, Bernt, additional, Zweier, Christiane, additional, Piard, Juliette, additional, Coubes, Christine, additional, Tran-Mau-Them, Frederic, additional, Safraou, Hana, additional, Innes, Micheil, additional, Gauthier, Julie, additional, Michaud, Jacques L, additional, Koboldt, Daniel C., additional, Sylvie, ODENT, additional, Willems, Marjolaine, additional, Tan, Wen-Hann, additional, Cogne, Benjamin, additional, Rieubland, Claudine, additional, Braun, Dominique, additional, McLean, Scott Douglas, additional, Platzer, Konrad, additional, Zacher, Pia, additional, Oppermann, Henry, additional, Evenepoel, Lucie, additional, BLANC, Pierre, additional, Khattabi, Laila El, additional, Haque, Neshatul, additional, Dsouza, Nikita R., additional, Zimmermann, Michael T, additional, Urrutia, Raul A, additional, Klee, Eric W, additional, Shen, Yiping, additional, Du, Hong-Zhen, additional, Qin, Zailong, additional, Liu, Chang-Mei, additional, and chen, xiaoli, additional

Published
2024
Full Text
View/download PDF

8. Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism

Author

Harms, Frederike Leonie, Girisha, Katta M, Hardigan, Andrew A, Kortüm, Fanny, Shukla, Anju, Alawi, Malik, Dalal, Ashwin, Brady, Lauren, Tarnopolsky, Mark, Bird, Lynne M, Ceulemans, Sophia, Bebin, Martina, Bowling, Kevin M, Hiatt, Susan M, Lose, Edward J, Primiano, Michelle, Chung, Wendy K, Juusola, Jane, Akdemir, Zeynep C, Bainbridge, Matthew, Charng, Wu-Lin, Drummond-Borg, Margaret, Eldomery, Mohammad K, El-Hattab, Ayman W, Saleh, Mohammed AM, Bézieau, Stéphane, Cogné, Benjamin, Isidor, Bertrand, Küry, Sébastien, Lupski, James R, Myers, Richard M, Cooper, Gregory M, and Kutsche, Kerstin

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Biotechnology, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Pediatric, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Adolescent, Adult, Amino Acid Substitution, Ataxia, Child, Child, Preschool, Chromatin, Cyclin-Dependent Kinase Inhibitor p21, Developmental Disabilities, Exome, Face, Female, Gene Expression Regulation, Genes, Reporter, HEK293 Cells, Humans, Intellectual Disability, Language Development Disorders, Male, Models, Molecular, Mosaicism, Mutation, Neurodevelopmental Disorders, Protein Transport, Syndrome, Transcription Factors, Transcription, Genetic, EBF3, de novo mutation, developmental delay, gene regulation, intellectual disability, transcription factor, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in ∼0.1% of individuals with unexplained neurodevelopmental disorders.

Published
2017

9. A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants

Author

Genetica, Genetica Klinische Genetica, Child Health, Borroto, Maria Carla, Michaud, Coralie, Hudon, Chloé, Agrawal, Pankaj B., Agre, Katherine, Applegate, Carolyn D., Beggs, Alan H., Bjornsson, Hans T., Callewaert, Bert, Chen, Mei Jan, Curry, Cynthia, Devinsky, Orrin, Dudding-Byth, Tracy, Fagan, Kelly, Finnila, Candice R., Gavrilova, Ralitza, Genetti, Casie A., Hiatt, Susan M., Hildebrandt, Friedhelm, Wojcik, Monica H., Kleefstra, Tjitske, Kolvenbach, Caroline M., Korf, Bruce R., Kruszka, Paul, Li, Hong, Litwin, Jessica, Marcadier, Julien, Platzer, Konrad, Blackburn, Patrick R., Reijnders, Margot R.F., Reutter, Heiko, Schanze, Ina, Shieh, Joseph T., Stevens, Cathy A., Valivullah, Zaheer, van den Boogaard, Marie José, Klee, Eric W., Campeau, Philippe M., Genetica, Genetica Klinische Genetica, Child Health, Borroto, Maria Carla, Michaud, Coralie, Hudon, Chloé, Agrawal, Pankaj B., Agre, Katherine, Applegate, Carolyn D., Beggs, Alan H., Bjornsson, Hans T., Callewaert, Bert, Chen, Mei Jan, Curry, Cynthia, Devinsky, Orrin, Dudding-Byth, Tracy, Fagan, Kelly, Finnila, Candice R., Gavrilova, Ralitza, Genetti, Casie A., Hiatt, Susan M., Hildebrandt, Friedhelm, Wojcik, Monica H., Kleefstra, Tjitske, Kolvenbach, Caroline M., Korf, Bruce R., Kruszka, Paul, Li, Hong, Litwin, Jessica, Marcadier, Julien, Platzer, Konrad, Blackburn, Patrick R., Reijnders, Margot R.F., Reutter, Heiko, Schanze, Ina, Shieh, Joseph T., Stevens, Cathy A., Valivullah, Zaheer, van den Boogaard, Marie José, Klee, Eric W., and Campeau, Philippe M.

Published
2024

10. A Genotype/Phenotype Study of KDM5B -Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.

Author

Borroto, Maria Carla, Michaud, Coralie, Hudon, Chloé, Agrawal, Pankaj B., Agre, Katherine, Applegate, Carolyn D., Beggs, Alan H., Bjornsson, Hans T., Callewaert, Bert, Chen, Mei-Jan, Curry, Cynthia, Devinsky, Orrin, Dudding-Byth, Tracy, Fagan, Kelly, Finnila, Candice R., Gavrilova, Ralitza, Genetti, Casie A., Hiatt, Susan M., Hildebrandt, Friedhelm, and Wojcik, Monica H.

Subjects
MISSENSE mutation, FACIAL abnormalities, INTELLECTUAL development, SLEEP disorders, INTELLECTUAL disabilities
Abstract

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals' family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

11. Long-read genome sequencing and variant reanalysis increase diagnostic yield in neurodevelopmental disorders

Author

Hiatt, Susan M, primary, Lawlor, James MJ, additional, Handley, Lori H, additional, Latner, Donald R, additional, Bonnstetter, Zachary T, additional, Finnila, Candice R, additional, Thompson, Michelle L, additional, Boston, Lori Beth, additional, Williams, Melissa, additional, Rodriguez Nunez, Ivan, additional, Jenkins, Jerry, additional, Kelley, Whitley V, additional, Bebin, E Martina, additional, Lopez, Michael A, additional, Hurst, Anna CE, additional, Korf, Bruce R, additional, Schmutz, Jeremy, additional, Grimwood, Jane, additional, and Cooper, Gregory M, additional

Published
2024
Full Text
View/download PDF

12. Current status and new features of the Consensus Coding Sequence database.

Author

Farrell, Catherine, OLeary, Nuala, Harte, Rachel, Loveland, Jane, Wilming, Laurens, Wallin, Craig, Diekhans, Mark, Barrell, Daniel, Searle, Stephen, Aken, Bronwen, Hiatt, Susan, Frankish, Adam, Suner, Marie-Marthe, Rajput, Bhanu, Steward, Charles, Brown, Garth, Bennett, Ruth, Murphy, Michael, Wu, Wendy, Kay, Mike, Hart, Jennifer, Rajan, Jeena, Weber, Janet, Snow, Catherine, Riddick, Lillian, Hunt, Toby, Webb, David, Thomas, Mark, Tamez, Pamela, Rangwala, Sanjida, McGarvey, Kelly, Pujar, Shashikant, Shkeda, Andrei, Mudge, Jonathan, Gonzalez, Jose, Gilbert, James, Trevanion, Stephen, Baertsch, Robert, Harrow, Jennifer, Hubbard, Tim, Ostell, James, Pruitt, Kim, and Haussler, David

Subjects
Animals, Databases, Genetic, Exons, Genomics, Humans, Internet, Mice, Molecular Sequence Annotation, Proteins, Sequence Analysis
Abstract

The Consensus Coding Sequence (CCDS) project (http://www.ncbi.nlm.nih.gov/CCDS/) is a collaborative effort to maintain a dataset of protein-coding regions that are identically annotated on the human and mouse reference genome assemblies by the National Center for Biotechnology Information (NCBI) and Ensembl genome annotation pipelines. Identical annotations that pass quality assurance tests are tracked with a stable identifier (CCDS ID). Members of the collaboration, who are from NCBI, the Wellcome Trust Sanger Institute and the University of California Santa Cruz, provide coordinated and continuous review of the dataset to ensure high-quality CCDS representations. We describe here the current status and recent growth in the CCDS dataset, as well as recent changes to the CCDS web and FTP sites. These changes include more explicit reporting about the NCBI and Ensembl annotation releases being compared, new search and display options, the addition of biologically descriptive information and our approach to representing genes for which support evidence is incomplete. We also present a summary of recent and future curation targets.

Published
2014

13. Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect

Author

Nizon, Mathilde, Laugel, Vincent, Flanigan, Kevin M., Pastore, Matthew, Waldrop, Megan A., Rosenfeld, Jill A., Marom, Ronit, Xiao, Rui, Gerard, Amanda, Pichon, Olivier, Le Caignec, Cédric, Gérard, Marion, Dieterich, Klaus, Truitt Cho, Megan, McWalter, Kirsty, Hiatt, Susan, Thompson, Michelle L., Bézieau, Stéphane, Wadley, Alexandrea, Wierenga, Klaas J., Egly, Jean-Marc, and Isidor, Bertrand

Published
2019
Full Text
View/download PDF

14. Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature

Author

Torti, Erin, Keren, Boris, Palmer, Elizabeth E., Zhu, Zehua, Afenjar, Alexandra, Anderson, Ilse. J., Andrews, Marisa V., Atkinson, Celia, Au, Margaret, Berry, Susan A., Bowling, Kevin M., Boyle, Jackie, Buratti, Julien, Cathey, Sara S., Charles, Perrine, Cogne, Benjamin, Courtin, Thomas, Escobar, Luis F., Finley, Sabra Ledare, Graham, Jr., John M., Grange, Dorothy K., Heron, Delphine, Hewson, Stacy, Hiatt, Susan M., Hibbs, Kathleen A., Jayakar, Parul, Kalsner, Louisa, Larcher, Lise, Lesca, Gaetan, Mark, Paul R., Miller, Kathryn, Nava, Caroline, Nizon, Mathilde, Pai, G. Shashidhar, Pappas, John, Parsons, Gretchen, Payne, Katelyn, Putoux, Audrey, Rabin, Rachel, Sabatier, Isabelle, Shinawi, Marwan, Shur, Natasha, Skinner, Steven A., Valence, Stephanie, Warren, Hannah, Whalen, Sandra, Crunk, Amy, Douglas, Ganka, Monaghan, Kristin G., Person, Richard E., Willaert, Rebecca, Solomon, Benjamin D., and Juusola, Jane

Published
2019
Full Text
View/download PDF

17. De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder

Author

Snijders Blok, Lot, Hiatt, Susan M., Bowling, Kevin M., Prokop, Jeremy W., Engel, Krysta L., Cochran, J. Nicholas, Bebin, E. Martina, Bijlsma, Emilia K., Ruivenkamp, Claudia A. L., Terhal, Paulien, Simon, Marleen E. H., Smith, Rosemarie, Hurst, Jane A., The DDD study, McLaughlin, Heather, Person, Richard, Crunk, Amy, Wangler, Michael F., Streff, Haley, Symonds, Joseph D., Zuberi, Sameer M., Elliott, Katherine S., Sanders, Victoria R., Masunga, Abigail, Hopkin, Robert J., Dubbs, Holly A., Ortiz-Gonzalez, Xilma R., Pfundt, Rolph, Brunner, Han G., Fisher, Simon E., Kleefstra, Tjitske, and Cooper, Gregory M.

Published
2018
Full Text
View/download PDF

18. Parents’ Perspectives on the Utility of Genomic Sequencing in the Neonatal Intensive Care Unit

Author

Lemke, Amy A., primary, Thompson, Michelle L., additional, Gimpel, Emily C., additional, McNamara, Katelyn C., additional, Rich, Carla A., additional, Finnila, Candice R., additional, Cochran, Meagan E., additional, Lawlor, James M. J., additional, East, Kelly M., additional, Bowling, Kevin M., additional, Latner, Donald R., additional, Hiatt, Susan M., additional, Amaral, Michelle D., additional, Kelley, Whitley V., additional, Greve, Veronica, additional, Gray, David E., additional, Felker, Stephanie A., additional, Meddaugh, Hannah, additional, Cannon, Ashley, additional, Luedecke, Amanda, additional, Jackson, Kelly E., additional, Hendon, Laura G., additional, Janani, Hillary M., additional, Johnston, Marla, additional, Merin, Lee Ann, additional, Deans, Sarah L., additional, Tuura, Carly, additional, Hughes, Trent, additional, Williams, Heather, additional, Laborde, Kelly, additional, Neu, Matthew B., additional, Patrick-Esteve, Jessica, additional, Hurst, Anna C. E., additional, Kirmse, Brian M., additional, Savich, Renate, additional, Spedale, Steven B., additional, Knight, Sara J., additional, Barsh, Gregory S., additional, Korf, Bruce R., additional, Cooper, Gregory M., additional, and Brothers, Kyle B., additional

Published
2023
Full Text
View/download PDF

19. 338 The Alabama Genomic Health Initiative: Integrating Genomic Medicine into Primary Care

Author

Limdi, Nita A, primary, Absher, Devin, additional, Asif, Irf, additional, Bateman, Lori, additional, Barsh, Greg, additional, Bowling, Kevin M., additional, Cooper, Gregory M., additional, Davis, Brittney H., additional, East, Kelly M., additional, Finnila, Candice R., additional, Goff, Blake, additional, Hiatt, Susan, additional, Kelly, Melissa, additional, Kelley, Whitley V., additional, Korf, Bruce R., additional, Latner, Donald R., additional, Lawlor, James, additional, May, Thomas, additional, Might, Matt, additional, Moss, Irene P., additional, Nakano-Okuno, Mariko, additional, Osborne, Tiffany, additional, Sodeke, Stephen, additional, Stout, Adriana, additional, and Thompson, Michelle L., additional

Published
2023
Full Text
View/download PDF

20. Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype

Author

Hiatt, Susan M., primary, Trajkova, Slavica, additional, Sebastiano, Matteo Rossi, additional, Partridge, E. Christopher, additional, Abidi, Fatima E., additional, Anderson, Ashlyn, additional, Ansar, Muhammad, additional, Antonarakis, Stylianos E., additional, Azadi, Azadeh, additional, Bachmann-Gagescu, Ruxandra, additional, Bartuli, Andrea, additional, Benech, Caroline, additional, Berkowitz, Jennifer L., additional, Betti, Michael J., additional, Brusco, Alfredo, additional, Cannon, Ashley, additional, Caron, Giulia, additional, Chen, Yanmin, additional, Cochran, Meagan E., additional, Coleman, Tanner F., additional, Crenshaw, Molly M., additional, Cuisset, Laurence, additional, Curry, Cynthia J., additional, Darvish, Hossein, additional, Demirdas, Serwet, additional, Descartes, Maria, additional, Douglas, Jessica, additional, Dyment, David A., additional, Elloumi, Houda Zghal, additional, Ermondi, Giuseppe, additional, Faoucher, Marie, additional, Farrow, Emily G., additional, Felker, Stephanie A., additional, Fisher, Heather, additional, Hurst, Anna C.E., additional, Joset, Pascal, additional, Kelly, Melissa A., additional, Kmoch, Stanislav, additional, Leadem, Benjamin R., additional, Lyons, Michael J., additional, Macchiaiolo, Marina, additional, Magner, Martin, additional, Mandrile, Giorgia, additional, Mattioli, Francesca, additional, McEown, Megan, additional, Meadows, Sarah K., additional, Medne, Livija, additional, Meeks, Naomi J.L., additional, Montgomery, Sarah, additional, Napier, Melanie P., additional, Natowicz, Marvin, additional, Newberry, Kimberly M., additional, Niceta, Marcello, additional, Noskova, Lenka, additional, Nowak, Catherine B., additional, Noyes, Amanda G., additional, Osmond, Matthew, additional, Prijoles, Eloise J., additional, Pugh, Jada, additional, Pullano, Verdiana, additional, Quélin, Chloé, additional, Rahimi-Aliabadi, Simin, additional, Rauch, Anita, additional, Redon, Sylvia, additional, Reymond, Alexandre, additional, Schwager, Caitlin R., additional, Sellars, Elizabeth A., additional, Scheuerle, Angela E., additional, Shukarova-Angelovska, Elena, additional, Skraban, Cara, additional, Stolerman, Elliot, additional, Sullivan, Bonnie R., additional, Tartaglia, Marco, additional, Thiffault, Isabelle, additional, Uguen, Kevin, additional, Umaña, Luis A., additional, van Bever, Yolande, additional, van der Crabben, Saskia N., additional, van Slegtenhorst, Marjon A., additional, Waisfisz, Quinten, additional, Washington, Camerun, additional, Rodan, Lance H., additional, Myers, Richard M., additional, and Cooper, Gregory M., additional

Published
2023
Full Text
View/download PDF

21. Poison exon annotations improve the yield of clinically relevant variants in genomic diagnostic testing

Author

Felker, Stephanie A, primary, Lawlor, James MJ, additional, Hiatt, Susan M, additional, Thompson, Michelle L, additional, Latner, Donald R, additional, Finnila, Candice R, additional, Bowling, Kevin M, additional, Bonnstetter, Zachary T, additional, Bonini, Katherine E, additional, Kelly, Nicole R, additional, Kelley, Whitley V, additional, Hurst, Anna CE, additional, Kelly, Melissa A, additional, Nakouzi, Ghunwa, additional, Hendon, Laura G, additional, Bebin, E Martina, additional, Kenny, Eimear E, additional, and Cooper, Gregory M, additional

Published
2023
Full Text
View/download PDF

22. Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype

Author

Hiatt, Susan M, Trajkova, Slavica, Sebastiano, Matteo Rossi, Partridge, E Christopher, et al, Bachmann-Gagescu, Ruxandra, Rauch, Anita, and University of Zurich

Subjects
10036 Medical Clinic, 10039 Institute of Medical Genetics, chromatin modifiers, ZMYM3X, 570 Life sciences, biology, 610 Medicine & health, transcriptional coregulators, linked intellectual disability, neurodevelopmental disorder, 10124 Institute of Molecular Life Sciences
Published
2023

23. Deleterious, protein-altering variants in the X-linked transcriptional coregulator ZMYM3 in 22 individuals with a neurodevelopmental delay phenotype

Author

Hiatt, Susan M, Trajkova, Slavica, Sebastiano, Matteo Rossi, Partridge, E Christopher, et al, Bachmann-Gagescu, Ruxandra, Rauch, Anita, and University of Zurich

Subjects
10039 Institute of Medical Genetics, ZMYM3, chromatin modifiers, 570 Life sciences, biology, 610 Medicine & health, transcriptional coregulators, linked intellectual disability, neurodevelopmental disorder
Published
2022

24. Deleterious, protein-altering variants in the X-linked transcriptional coregulator ZMYM3 in 22 individuals with a neurodevelopmental delay phenotype

Author

Hiatt, Susan M., primary, Trajkova, Slavica, additional, Sebastiano, Matteo Rossi, additional, Partridge, E. Christopher, additional, Abidi, Fatima E., additional, Anderson, Ashlyn, additional, Ansar, Muhammad, additional, Antonarakis, Stylianos E., additional, Azadi, Azadeh, additional, Bachmann-Gagescu, Ruxandra, additional, Bartuli, Andrea, additional, Benech, Caroline, additional, Berkowitz, Jennifer L., additional, Betti, Michael J., additional, Brusco, Alfredo, additional, Cannon, Ashley, additional, Caron, Giulia, additional, Chen, Yanmin, additional, Crenshaw, Molly M., additional, Cuisset, Laurence, additional, Curry, Cynthia J., additional, Darvish, Hossein, additional, Demirdas, Serwet, additional, Descartes, Maria, additional, Douglas, Jessica, additional, Dyment, David A., additional, Elloumi, Houda Zghal, additional, Ermondi, Giuseppe, additional, Faoucher, Marie, additional, Farrow, Emily G., additional, Felker, Stephanie A., additional, Fisher, Heather, additional, Hurst, Anna C. E., additional, Joset, Pascal, additional, Kmoch, Stanislav, additional, Leadem, Benjamin R., additional, Macchiaiolo, Marina, additional, Magner, Martin, additional, Mandrile, Giorgia, additional, Mattioli, Francesca, additional, McEown, Megan, additional, Meadows, Sarah K., additional, Medne, Livija, additional, Meeks, Naomi J. L., additional, Montgomery, Sarah, additional, Napier, Melanie P., additional, Natowicz, Marvin, additional, Newberry, Kimberly M., additional, Niceta, Marcello, additional, Noskova, Lenka, additional, Nowak, Catherine, additional, Noyes, Amanda G., additional, Osmond, Matthew, additional, Pullano, Verdiana, additional, Quélin, Chloé, additional, Rahimi-Aliabadi, Simin, additional, Rauch, Anita, additional, Redon, Sylvia, additional, Reymond, Alexandre, additional, Schwager, Caitlin R., additional, Sellars, Elizabeth A., additional, Scheuerle, Angela, additional, Shukarova-Angelovska, Elena, additional, Skraban, Cara, additional, Sullivan, Bonnie R., additional, Tartaglia, Marco, additional, Thiffault, Isabelle, additional, Uguen, Kevin, additional, Umaña, Luis A., additional, van Bever, Yolande, additional, van der Crabben, Saskia N., additional, van Slegtenhorst, Marjon A., additional, Waisfisz, Quinten, additional, Myers, Richard M., additional, and Cooper, Gregory M., additional

Published
2022
Full Text
View/download PDF

25. Genome sequencing as a first-line diagnostic test for hospitalized infants

Author

Bowling, Kevin M., primary, Thompson, Michelle L., additional, Finnila, Candice R., additional, Hiatt, Susan M., additional, Latner, Donald R., additional, Amaral, Michelle D., additional, Lawlor, James M.J., additional, East, Kelly M., additional, Cochran, Meagan E., additional, Greve, Veronica, additional, Kelley, Whitley V., additional, Gray, David E., additional, Felker, Stephanie A., additional, Meddaugh, Hannah, additional, Cannon, Ashley, additional, Luedecke, Amanda, additional, Jackson, Kelly E., additional, Hendon, Laura G., additional, Janani, Hillary M., additional, Johnston, Marla, additional, Merin, Lee Ann, additional, Deans, Sarah L., additional, Tuura, Carly, additional, Williams, Heather, additional, Laborde, Kelly, additional, Neu, Matthew B., additional, Patrick-Esteve, Jessica, additional, Hurst, Anna C.E., additional, Kandasamy, Jegen, additional, Carlo, Wally, additional, Brothers, Kyle B., additional, Kirmse, Brian M., additional, Savich, Renate, additional, Superneau, Duane, additional, Spedale, Steven B., additional, Knight, Sara J., additional, Barsh, Gregory S., additional, Korf, Bruce R., additional, and Cooper, Gregory M., additional

Published
2022
Full Text
View/download PDF

28. eP370: SouthSeq: Genome sequencing for a diverse population of hospitalized infants

Author

Latner, Donald, primary, Bowling, Kevin, additional, Thompson, Michelle, additional, Finnila, Candice, additional, Hiatt, Susan, additional, Amaral, Michelle, additional, Lawlor, James, additional, East, Kelly, additional, Cochran, Meagan, additional, Greve, Veronica, additional, Kelley, Whitley V., additional, Gray, David, additional, Felker, Stephanie, additional, Meddaugh, Hannah, additional, Cannon, Ashley, additional, Luedecke, Amanda, additional, Jackson, Kelly, additional, Hendon, Laura, additional, Janani, Hillary, additional, Johnston, Marla, additional, Merin, Lee Ann, additional, Deans, Sarah, additional, Tuura, Carly, additional, Williams, Heather, additional, Laborde, Kelly, additional, Neu, Matthew, additional, Patrick-Esteve, Jessica, additional, Hurst, Anna, additional, Kandasamy, Jegen, additional, Carlo, Waldemar, additional, Brothers, Kyle, additional, Kirmse, Brian, additional, Savich, Renate, additional, Superneau, Duane, additional, Spedale, Steven, additional, Knight, Sara, additional, Barsh, Gregory, additional, Korf, Bruce, additional, and Cooper, Gregory, additional

Published
2022
Full Text
View/download PDF

29. eP141: Expansion of long-read genome sequencing for the molecular diagnosis of neurodevelopmental disorders and multiple congenital anomalies

Author

Hiatt, Susan, primary, Lawlor, James, additional, Handley, Lori, additional, Bonnstetter, Zachary, additional, Jenkins, Jerry, additional, Lovell, John, additional, Holt, James, additional, Finnila, Candice, additional, Thompson, Michelle, additional, Latner, Donald, additional, Partridge, Christopher, additional, Plott, Christopher, additional, Boston, Lori Beth, additional, Williams, Melissa, additional, Bowling, Kevin, additional, Grimwood, Jane, additional, Schmutz, Jeremy, additional, and Cooper, Gregory, additional

Published
2022
Full Text
View/download PDF

30. eP425: Parental impact of genome sequencing during the neonatal period

Author

Brothers, Kyle, primary, Rich, Carla, additional, Gimpel, Emily, additional, East, Kelly, additional, Cochran, Meagan, additional, Greve, Veronica, additional, Kelley, Whitley V., additional, Jackson, Kelly, additional, Hendon, Laura, additional, Luedecke, Amanda, additional, Janani, Hillary, additional, Meddaugh, Hannah, additional, Latner, Donald, additional, Bowling, Kevin, additional, Thompson, Michelle, additional, Finnila, Candice, additional, Hiatt, Susan, additional, Amaral, Michelle, additional, Lawlor, James, additional, Gray, David, additional, Felker, Stephanie, additional, Cannon, Ashley, additional, Johnston, Marla, additional, Merin, Lee Ann, additional, Deans, Sarah, additional, Tuura, Carly, additional, Williams, Heather, additional, Laborde, Kelly, additional, Neu, Matthew, additional, Patrick-Esteve, Jessica, additional, Hurst, Anna, additional, Kandasamy, Jegen, additional, Carlo, Waldemar, additional, Kirmse, Brian, additional, Savich, Renate, additional, Superneau, Duane, additional, Spedale, Steven, additional, Knight, Sara, additional, Barsh, Gregory, additional, Korf, Bruce, additional, and Cooper, Gregory, additional

Published
2022
Full Text
View/download PDF

32. Genome sequencing as a first-line diagnostic test for hospitalized newborns

Author

Bowling, Kevin M., primary, Thompson, Michelle L., additional, Finnila, Candice R., additional, Hiatt, Susan M., additional, Latner, Donald R., additional, Amaral, Michelle D., additional, Lawlor, James M.J., additional, East, Kelly M., additional, Cochran, Meagan E., additional, Greve, Veronica, additional, Kelley, Whitley V., additional, Gray, David E., additional, Felker, Stephanie A., additional, Meddaugh, Hanna, additional, Cannon, Ashley, additional, Luedecke, Amanda, additional, Jackson, Kelly E., additional, Hendon, Laura G., additional, Janani, Hillary M., additional, Johnston, Marla, additional, Merin, Lee Ann, additional, Deans, Sarah L., additional, Tuura, Carly, additional, Williams, Heather, additional, Laborde, Kelly, additional, Neu, Matthew B., additional, Patrick-Esteve, Jessica, additional, Hurst, Anna C.E., additional, Kandasamy, Jegen, additional, Carlo, Wally, additional, Brothers, Kyle B., additional, Kirmse, Brian M., additional, Savich, Renate, additional, Superneau, Duane, additional, Spedale, Steven B., additional, Knight, Sara J., additional, Barsh, Gregory S., additional, Korf, Bruce R., additional, and Cooper, Gregory M., additional

Published
2021
Full Text
View/download PDF

33. RefSeq: an update on mammalian reference sequences

Author

Pruitt, Kim D., Brown, Garth R., Hiatt, Susan M., Thibaud-Nissen, Françoise, Astashyn, Alexander, Ermolaeva, Olga, Farrell, Catherine M., Hart, Jennifer, Landrum, Melissa J., McGarvey, Kelly M., Murphy, Michael R., OʼLeary, Nuala A., Pujar, Shashikant, Rajput, Bhanu, Rangwala, Sanjida H., Riddick, Lillian D., Shkeda, Andrei, Sun, Hanzhen, Tamez, Pamela, Tully, Raymond E., Wallin, Craig, Webb, David, Weber, Janet, Wu, Wendy, DiCuccio, Michael, Kitts, Paul, Maglott, Donna R., Murphy, Terence D., and Ostell, James M.

Published
2014
Full Text
View/download PDF

34. Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy

Author

Voisin, Norine, primary, Schnur, Rhonda E., additional, Douzgou, Sofia, additional, Hiatt, Susan M., additional, Rustad, Cecilie F., additional, Brown, Natasha J., additional, Earl, Dawn L., additional, Keren, Boris, additional, Levchenko, Olga, additional, Geuer, Sinje, additional, Verheyen, Sarah, additional, Johnson, Diana, additional, Zarate, Yuri A., additional, Hančárová, Miroslava, additional, Amor, David J., additional, Bebin, E. Martina, additional, Blatterer, Jasmin, additional, Brusco, Alfredo, additional, Cappuccio, Gerarda, additional, Charrow, Joel, additional, Chatron, Nicolas, additional, Cooper, Gregory M., additional, Courtin, Thomas, additional, Dadali, Elena, additional, Delafontaine, Julien, additional, Del Giudice, Ennio, additional, Doco, Martine, additional, Douglas, Ganka, additional, Eisenkölbl, Astrid, additional, Funari, Tara, additional, Giannuzzi, Giuliana, additional, Gruber-Sedlmayr, Ursula, additional, Guex, Nicolas, additional, Heron, Delphine, additional, Holla, Øystein L., additional, Hurst, Anna C.E., additional, Juusola, Jane, additional, Kronn, David, additional, Lavrov, Alexander, additional, Lee, Crystle, additional, Lorrain, Séverine, additional, Merckoll, Else, additional, Mikhaleva, Anna, additional, Norman, Jennifer, additional, Pradervand, Sylvain, additional, Prchalová, Darina, additional, Rhodes, Lindsay, additional, Sanders, Victoria R., additional, Sedláček, Zdeněk, additional, Seebacher, Heidelis A., additional, Sellars, Elizabeth A., additional, Sirchia, Fabio, additional, Takenouchi, Toshiki, additional, Tanaka, Akemi J., additional, Taska-Tench, Heidi, additional, Tønne, Elin, additional, Tveten, Kristian, additional, Vitiello, Giuseppina, additional, Vlčková, Markéta, additional, Uehara, Tomoko, additional, Nava, Caroline, additional, Yalcin, Binnaz, additional, Kosaki, Kenjiro, additional, Donnai, Dian, additional, Mundlos, Stefan, additional, Brunetti-Pierri, Nicola, additional, Chung, Wendy K., additional, and Reymond, Alexandre, additional

Published
2021
Full Text
View/download PDF

35. The Therapeutic Odyssey: Positioning Genomic Sequencing in the Search for a Child’s Best Possible Life

Author

Childerhose, Janet Elizabeth, primary, Rich, Carla, additional, East, Kelly M., additional, Kelley, Whitley V., additional, Simmons, Shirley, additional, Finnila, Candice R., additional, Bowling, Kevin, additional, Amaral, Michelle, additional, Hiatt, Susan M., additional, Thompson, Michelle, additional, Gray, David E., additional, Lawlor, James M. J., additional, Myers, Richard M., additional, Barsh, Gregory S., additional, Lose, Edward J., additional, Bebin, Martina E., additional, Cooper, Greg M., additional, and Brothers, Kyle Bertram, additional

Published
2021
Full Text
View/download PDF

36. SouthSeq: genome sequencing as a frontline genetic test in the NICU

Author

Amaral, Michelle, primary, Thompson, Michelle, additional, Bowling, Kevin, additional, Finnila, Candice, additional, Hiatt, Susan M., additional, Latner, Donald, additional, Kelley, Whitley V., additional, East, Kelly, additional, Greve, Veronica, additional, Cochran, Meagan, additional, Gray, David, additional, Lawlor, James, additional, Meddaugh, Hannah, additional, Cannon, Ashley, additional, Luedecke, Amanda, additional, Jackson, Kelly, additional, Hendon, Laura, additional, Janani, Hillary, additional, Johnston, Marla, additional, Merin, Lee Ann, additional, Deans, Sarah, additional, Tuura, Carly, additional, Hughes, Trent, additional, Williams, Heather, additional, Laborde, Kelly, additional, Patrick-Esteve, Jessica, additional, Hurst, Anna, additional, Brothers, Kyle, additional, Savich, Renate, additional, Spedale, Steven, additional, Knight, Sara, additional, Barsh, Gregory, additional, Korf, Bruce, additional, and Cooper, Gregory, additional

Published
2021
Full Text
View/download PDF

37. A state-based approach to genomics for rare disease and population screening

Author

East, Kelly M., primary, Kelley, Whitley V., additional, Cannon, Ashley, additional, Cochran, Meagan E., additional, Moss, Irene P., additional, May, Thomas, additional, Nakano-Okuno, Mariko, additional, Sodeke, Stephen O., additional, Edberg, Jeffrey C., additional, Cimino, James J., additional, Fouad, Mona, additional, Curry, William A., additional, Hurst, Anna C.E., additional, Bowling, Kevin M., additional, Thompson, Michelle L., additional, Bebin, E. Martina, additional, Johnson, Robert D., additional, Acemgil, Aras, additional, Crossman, David K., additional, Finnila, Candice R., additional, Gray, David E., additional, Greve, Veronica, additional, Hardy, Sharonda, additional, Hiatt, Susan M., additional, Latner, Donald R., additional, Lawlor, James M.J., additional, Miskell, Edrika L., additional, Narmore, Whitney, additional, Schach, Julie H., additional, Cooper, Gregory M., additional, Might, Matthew, additional, Barsh, Gregory S., additional, and Korf, Bruce R., additional

Published
2021
Full Text
View/download PDF

39. Long-read genome sequencing for the molecular diagnosis of neurodevelopmental disorders

Author

Hiatt, Susan, primary, Lawlor, James, additional, Handley, Lori, additional, Ramaker, Ryne, additional, Rogers, Brianne, additional, Partridge, Christopher, additional, Boston, Lori Beth, additional, Williams, Melissa, additional, Plott, Christopher, additional, Jenkins, Jerry, additional, Gray, David, additional, Holt, James, additional, Bowling, Kevin, additional, Bebin, Martina, additional, Grimwood, Jane, additional, Schmutz, Jeremy, additional, and Cooper, Gregory, additional

Published
2021
Full Text
View/download PDF

40. Long-read genome sequencing for the molecular diagnosis of neurodevelopmental disorders

Author

Hiatt, Susan M., primary, Lawlor, James M.J., additional, Handley, Lori H., additional, Ramaker, Ryne C., additional, Rogers, Brianne B., additional, Partridge, E. Christopher, additional, Boston, Lori Beth, additional, Williams, Melissa, additional, Plott, Christopher B., additional, Jenkins, Jerry, additional, Gray, David E., additional, Holt, James M., additional, Bowling, Kevin M., additional, Bebin, E. Martina, additional, Grimwood, Jane, additional, Schmutz, Jeremy, additional, and Cooper, Gregory M., additional

Published
2021
Full Text
View/download PDF

41. De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature

Author

Nambot, Sophie, Faivre, Laurence, Mirzaa, Ghayda, Thevenon, Julien, Bruel, Ange-Line, Mosca-Boidron, Anne-Laure, Masurel-Paulet, Alice, Goldenberg, Alice, Le Meur, Nathalie, Charollais, Aude, Mignot, Cyril, Petit, Florence, Rossi, Massimiliano, Metreau, Julia, Layet, Valérie, Amram, Daniel, Boute-Bénéjean, Odile, Bhoj, Elizabeth, Cousin, Margot, Kruisselbrink, Teresa, Lanpher, Brendan, Klee, Eric, Fiala, Elise, Grange, Dorothy, Meschino, Wendy, Hiatt, Susan, Cooper, Gregory, Olivié, Hilde, Smith, Wendy, Dumas, Meghan, Lehman, Anna, Inglese, Cara, Nizon, Mathilde, Guerrini, Renzo, Vetro, Annalisa, Kaplan, Eitan, Miramar, Dolores, van Gils, Julien, Fergelot, Patricia, Bodamer, Olaf, Herkert, Johanna, Pajusalu, Sander, Õunap, Katrin, Filiano, James, Smol, Thomas, Piton, Amélie, Gérard, Bénédicte, Chantot-Bastaraud, Sandra, Bienvenu, Thierry, Li, Dong, Juusola, Jane, Devriendt, Koen, Bilan, Frederic, Poé, Charlotte, Chevarin, Martin, Jouan, Thibaud, Tisserant, Emilie, Rivière, Jean-Baptiste, Tran Mau-Them, Frédéric, Philippe, Christophe, Duffourd, Yannis, Dobyns, William, Hevner, Robert, Thauvin-Robinet, Christel, Couvet, Sandrine, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Department of Pediatrics [Seattle], University of Washington [Seattle], Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service de pédiatrie médicale et médecine de l'adolescent [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Service de Génétique [CHU Lyon] (Centre de pathologie de l'Est), Hospices civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetics of Neurodevelopment (GENDEV), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Service de Neurologie Pédiatrique [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Département de génétique (groupe hospitalier le Havre), Groupe Hospitalier du Havre, Centre Hospitalier Intercommunal de Créteil (CHIC), Department of Pediatrics [Philadelphia, PA, USA] (Division of Genetics), Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics [Philadelphia, PA, USA], Mayo Clinic [Rochester], Department of Pediatrics [Saint Louis, MO, USA] (Division of Genetics and Genomic Medicine), Washington University in Saint Louis (WUSTL), Department of Genetics [Saint-Louis], HudsonAlpha Institute for Biotechnology [Huntsville, AL], University Hospitals Leuven [Leuven], Maine Medical Center, University of British Columbia [Vancouver], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Meyer Children's Hospital [Florence, Italie], Università degli Studi di Firenze = University of Florence (UniFI), CHU Bordeaux [Bordeaux], Department of Genetics [Boston], Harvard Medical School [Boston] (HMS), University Medical Center Groningen [Groningen] (UMCG), University of Tartu, Dartmouth Hitchcock Medical Center [Lebanon, NH, USA] (DHMC), Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], UF de Génétique chromosomique [CHU Trousseau], Service de Génétique et Biologie Moléculaires [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), GeneDx [Gaithersburg, MD, USA], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)

Subjects
Proband, Candidate gene, INTELLECTUAL DISABILITY, MESH: Hippocampus, [SDV]Life Sciences [q-bio], MESH: Cognition, MESH: Neocortex, MESH: Child, Intellectual disability, MESH: Craniofacial Abnormalities, MESH: Animals, MESH: Syndrome, Genetics (clinical), Genetics, PROGENITORS, biology, Phenotype, NEOCORTEX, [SDV] Life Sciences [q-bio], EXPRESSION, GENES, MESH: Mutation, MESH: T-Box Domain Proteins, MESH: Autistic Disorder, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, Article, REGION, MESH: Intellectual Disability, NEUROGENESIS, Dysgenesis, FEZF2, medicine, MESH: Mice, MESH: Adolescent, MESH: Humans, MUTATIONS, business.industry, MESH: Child, Preschool, MESH: Adult, medicine.disease, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, Autism, TBR1, business, Neurocognitive, MESH: Female
Abstract

International audience; TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.

Published
2020
Full Text
View/download PDF

42. Home visiting by paraprofessionals and by nurses: a randomized, controlled trial

Author

Olds, David L., Robinson, JoAnn, Spalding, Ruth, Luckey, Dennis W., Pettitt, Lisa M., Henderson, Charles R., Jr, Ng, Rosanna K., Sheff, Karen L., Korfmacher, Jon, Hiatt, Susan, and Talmi, Ayelet

Subjects
American Academy of Pediatrics -- Standards, House calls (Medicine) -- Health aspects
Abstract

Objective. To examine the effectiveness of home visiting by paraprofessionals and by nurses as separate means of improving maternal and child health when both types of visitors are trained in a program model that has demonstrated effectiveness when delivered by nurses. Methods. A randomized, controlled trial was conducted in public- and private-care settings in Denver, Colorado. One thousand one hundred seventy-eight consecutive pregnant women with no previous live births who were eligible for Medicaid or who had no private health insurance were invited to participate. Seven hundred thirty-five women were randomized to control, paraprofessional, or nurse conditions. Nurses completed an average of 6.5 home visits during pregnancy and 21 visits from birth to the children's second birthdays. Paraprofessionals completed an average of 6.3 home visits during pregnancy and 16 visits from birth to the children's second birthdays. The main outcomes consisted of changes in women's urine cotinine over the course of pregnancy; women's use of ancillary services during pregnancy; subsequent pregnancies and births, educational achievement, workforce participation, and use of welfare; mother-infant responsive interaction; families' home environments; infants' emotional vulnerability in response to fear stimuli and low emotional vitality in response to joy and anger stimuli; and children's language and mental development, temperament, and behavioral problems. Results. Paraprofessional-visited mother-child pairs in which the mother had low psychological resources interacted with one another more responsively than their control-group counterparts (99.45 vs 97.54 standard score points). There were no other statistically significant paraprofessional effects. In contrast to their control-group counterparts, nurse-visited smokers had greater reductions in cotinine levels from intake to the end of pregnancy (259.0 vs 12.32 ng/ mL); by the study child's second birthday, women visited by nurses had fewer subsequent pregnancies (29% vs 41%) and births (12% vs 19%); they delayed subsequent pregnancies for longer intervals; and during the second year after the birth of their first child, they worked more than women in the control group (6.83 vs 5.65 months). Nurse-visited mother-child pairs interacted with one another more responsively than those in the control group (100.31 vs 98.99 standard score points). At 6 months of age, nurse-visited infants, in contrast to their control-group counterparts, were less likely to exhibit emotional vulnerability in response to fear stimuli (16% vs 25%) and nurse-visited infants born to women with low psychological resources were less likely to exhibit low emotional vitality in response to joy and anger stimuli (24% vs 40% and 13% vs 33%). At 21 months, nurse-visited children born to women with low psychological resources were less likely to exhibit language delays (7% vs 18%); and at 24 months, they exhibited superior mental development (90.18 vs 86.20 Mental Development Index scores) than their control-group counterparts. There were no statistically significant program effects for the nurses on women's use of ancillary prenatal services, educational achievement, use of welfare, or their children's temperament or behavior problems. For most outcomes on which either visitor produced significant effects, the paraprofessionals typically had effects that were about half the size of those produced by nurses. Conclusions. When trained in a model program of prenatal and infancy home visiting, paraprofessionals produced small effects that rarely achieved statistical or clinical significance; the absence of statistical significance for some outcomes is probably attributable to limited statistical power to detect small effects. Nurses produced significant effects on a wide range of maternal and child outcomes. Pediatrics 2002;110:486-496; home visits, paraprofessionals, nurses, pregnancy, development. ABBREVIATIONS. SD, standard deviation; MDI, Mental Development Index., Home visiting has been promoted by the American Academy of Pediatrics as an important complement to office-based practice. (1) It has been advocated as a way to improve the outcomes [...]

Published
2002

43. Long-read genome sequencing for the diagnosis of neurodevelopmental disorders

Author

Hiatt, Susan M., primary, Lawlor, James M.J., additional, Handley, Lori H., additional, Ramaker, Ryne C., additional, Rogers, Brianne B., additional, Partridge, E. Christopher, additional, Boston, Lori Beth, additional, Williams, Melissa, additional, Plott, Christopher B., additional, Jenkins, Jerry, additional, Gray, David E., additional, Holt, James M., additional, Bowling, Kevin M., additional, Bebin, E. Martina, additional, Grimwood, Jane, additional, Schmutz, Jeremy, additional, and Cooper, Gregory M., additional

Published
2020
Full Text
View/download PDF

44. BAZ2B haploinsufficiency as a cause of developmental delay, intellectual disability, and autism spectrum disorder

Author

Scott, Tiana M., primary, Guo, Hui, additional, Eichler, Evan E., additional, Rosenfeld, Jill A., additional, Pang, Kaifang, additional, Liu, Zhandong, additional, Lalani, Seema, additional, Bi, Weimin, additional, Yang, Yaping, additional, Bacino, Carlos A., additional, Streff, Haley, additional, Lewis, Andrea M., additional, Koenig, Mary K., additional, Thiffault, Isabelle, additional, Bellomo, Allison, additional, Everman, David B., additional, Jones, Julie R., additional, Stevenson, Roger E., additional, Bernier, Raphael, additional, Gilissen, Christian, additional, Pfundt, Rolph, additional, Hiatt, Susan M., additional, Cooper, Gregory M., additional, Holder, Jimmy L., additional, and Scott, Daryl A., additional

Published
2020
Full Text
View/download PDF

45. ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder

Author

Carapito, Raphael, primary, Ivanova, Ekaterina L., additional, Morlon, Aurore, additional, Meng, Linyan, additional, Molitor, Anne, additional, Erdmann, Eva, additional, Kieffer, Bruno, additional, Pichot, Angélique, additional, Naegely, Lydie, additional, Kolmer, Aline, additional, Paul, Nicodème, additional, Hanauer, Antoine, additional, Tran Mau-Them, Frédéric, additional, Jean-Marçais, Nolwenn, additional, Hiatt, Susan M., additional, Cooper, Gregory M., additional, Tvrdik, Tatiana, additional, Muir, Alison M., additional, Dimartino, Clémantine, additional, Chopra, Maya, additional, Amiel, Jeanne, additional, Gordon, Christopher T., additional, Dutreux, Fabien, additional, Garde, Aurore, additional, Thauvin-Robinet, Christel, additional, Wang, Xia, additional, Leduc, Magalie S., additional, Phillips, Meredith, additional, Crawford, Heather P., additional, Kukolich, Mary K., additional, Hunt, David, additional, Harrison, Victoria, additional, Kharbanda, Mira, additional, Smigiel, Robert, additional, Gold, Nina, additional, Hung, Christina Y., additional, Viskochil, David H., additional, Dugan, Sarah L., additional, Bayrak-Toydemir, Pinar, additional, Joly-Helas, Géraldine, additional, Guerrot, Anne-Marie, additional, Schluth-Bolard, Caroline, additional, Rio, Marlène, additional, Wentzensen, Ingrid M., additional, McWalter, Kirsty, additional, Schnur, Rhonda E., additional, Lewis, Andrea M., additional, Lalani, Seema R., additional, Mensah-Bonsu, Noël, additional, Céraline, Jocelyn, additional, Sun, Zijie, additional, Ploski, Rafal, additional, Bacino, Carlos A., additional, Mefford, Heather C., additional, Faivre, Laurence, additional, Bodamer, Olaf, additional, Chelly, Jamel, additional, Isidor, Bertrand, additional, and Bahram, Seiamak, additional

Published
2020
Full Text
View/download PDF

46. CHARACTERISTICS OF VOLUNTEERS AND FAMILIES IN A NEONATAL HOME VISITATION PROJECT: THE KEMPE COMMUNITY CARING PROGRAM

Author

HIATT, SUSAN W., MICHALEK, PATTY, YOUNGE, PHYLLIS, MIYOSHI, THOMAS, and FRYER, EDWARD

Subjects
Evaluation research (Social action programs) -- Analysis, Family services -- Evaluation, Volunteer workers in community health services -- Services, Family and marriage, Sociology and social work
Abstract

Objective: The purpose of this paper is to review literature related to home visitation support for new families using volunteer visitors and to describe characteristics of volunteers of the Kempe Community Caring Program, a home visitor support program for first time parents. Suggestions for effectively utilizing volunteers in family support programs are made. Method: Program data was collected and reviewed on 592 volunteer home visitors and the 1,144 families they served. Several evaluations and assessments were performed in order to attempt to measure the success of the intervention. Motivation for volunteering, longevity with program, and the extent of sociodemographic match between visitor and client were reviewed and discussed. Results: Information on matched volunteer-client pairs was limited; however, speculations were made that neither motivation to participate nor sociodemographic match were critical factors in determining success of the intervention. Duration of volunteer participation was influenced by marital status, but not by age. Married volunteers stayed with the program significantly longer than unmarried volunteers. Low risk families demonstrated slightly improved confidence in parental function after receiving home visitation by a volunteer. Conclusion: This program suggests that new mothers may benefit from receiving the services of a volunteer home visitor; specifically, their confidence as parents and ability to establish positive relationships show slight improvement. Likewise, volunteers and families felt satisfied with the supportive relationships generated. In addition, a volunteer profile emerged which may be beneficial to similar programs' recruiting efforts. Key Words---Home visitation, New families, Volunteers.

Published
2000

47. Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder

Author

Hiatt, Susan M., Thompson, Michelle L., Prokop, Jeremy W., Lawlor, James M.J., Gray, David E., Bebin, E.Martina, Rinne, T.K., Kempers, M.J.E., Pfundt, R.P., Bon, B.W. van, McWalter, Kirsty, Cooper, Gregory M., Hiatt, Susan M., Thompson, Michelle L., Prokop, Jeremy W., Lawlor, James M.J., Gray, David E., Bebin, E.Martina, Rinne, T.K., Kempers, M.J.E., Pfundt, R.P., Bon, B.W. van, McWalter, Kirsty, and Cooper, Gregory M.

Abstract

Contains fulltext : 202785.pdf (publisher's version ) (Open Access)

Published
2019

48. Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size.

Author

Panoutsopoulos, Alexios, Panoutsopoulos, Alexios, Harlan De Crescenzo, Angelo, Kotzaeridou, Urania, Syrbe, Steffen, Anagnostou, Evdokia, Azage, Meron, Bend, Renee, Begtrup, Amber, Brown, Natasha, Büttner, Benjamin, Cho, Megan, Cooper, Gregory, Doering, Jan, Dubourg, Christèle, Everman, David, Hildebrand, Michael, Santos, Francis, Kellam, Barbara, Keller-Ramey, Jennifer, Lemke, Johannes, Liu, Shuxi, Niyazov, Dmitriy, Payne, Katelyn, Person, Richard, Quélin, Chloé, Schnur, Rhonda, Smith, Brooke, Strober, Jonathan, Walker, Susan, Wallis, Mathew, Walsh, Laurence, Yang, Sandra, Yuen, Ryan, Ziegler, Andreas, Sticht, Heinrich, Pride, Michael, Orosco, Lori, Martínez-Cerdeño, Verónica, Le Duc, Diana, Jamra, Rami, Hiatt, Susan, Crawley, Jacqueline, Scherer, Stephen, Zarbalis, Konstantinos, Giulivi, Cecilia, Silverman, Jill, Napoli, Eleonora, Panoutsopoulos, Alexios, Panoutsopoulos, Alexios, Harlan De Crescenzo, Angelo, Kotzaeridou, Urania, Syrbe, Steffen, Anagnostou, Evdokia, Azage, Meron, Bend, Renee, Begtrup, Amber, Brown, Natasha, Büttner, Benjamin, Cho, Megan, Cooper, Gregory, Doering, Jan, Dubourg, Christèle, Everman, David, Hildebrand, Michael, Santos, Francis, Kellam, Barbara, Keller-Ramey, Jennifer, Lemke, Johannes, Liu, Shuxi, Niyazov, Dmitriy, Payne, Katelyn, Person, Richard, Quélin, Chloé, Schnur, Rhonda, Smith, Brooke, Strober, Jonathan, Walker, Susan, Wallis, Mathew, Walsh, Laurence, Yang, Sandra, Yuen, Ryan, Ziegler, Andreas, Sticht, Heinrich, Pride, Michael, Orosco, Lori, Martínez-Cerdeño, Verónica, Le Duc, Diana, Jamra, Rami, Hiatt, Susan, Crawley, Jacqueline, Scherer, Stephen, Zarbalis, Konstantinos, Giulivi, Cecilia, Silverman, Jill, and Napoli, Eleonora

Abstract

The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microceph

Published
2019

49. Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder

Author

Hiatt, Susan M, Thompson, Michelle L, Prokop, Jeremy W, Lawlor, James M J, Gray, David E, Bebin, E Martina, Rinne, Tuula, Kempers, Marlies, Pfundt, Rolph, van Bon, Bregje W, Mignot, Cyril, Nava, Caroline, Depienne, Christel, Kalsner, Louisa, Rauch, Anita, Joset, Pascal, Bachmann-Gagescu, Ruxandra; https://orcid.org/0000-0002-3571-5271, Wentzensen, Ingrid M, McWalter, Kirsty, Cooper, Gregory M, Hiatt, Susan M, Thompson, Michelle L, Prokop, Jeremy W, Lawlor, James M J, Gray, David E, Bebin, E Martina, Rinne, Tuula, Kempers, Marlies, Pfundt, Rolph, van Bon, Bregje W, Mignot, Cyril, Nava, Caroline, Depienne, Christel, Kalsner, Louisa, Rauch, Anita, Joset, Pascal, Bachmann-Gagescu, Ruxandra; https://orcid.org/0000-0002-3571-5271, Wentzensen, Ingrid M, McWalter, Kirsty, and Cooper, Gregory M

Abstract

Developmental delay and intellectual disability (DD and ID) are heterogeneous phenotypes that arise in many rare monogenic disorders. Because of this rarity, developing cohorts with enough individuals to robustly identify disease-associated genes is challenging. Social-media platforms that facilitate data sharing among sequencing labs can help to address this challenge. Through one such tool, GeneMatcher, we identified nine DD- and/or ID-affected probands with a rare, heterozygous variant in the gene encoding the serine/threonine-protein kinase BRSK2. All probands have a speech delay, and most present with intellectual disability, motor delay, behavioral issues, and autism. Six of the nine variants are predicted to result in loss of function, and computational modeling predicts that the remaining three missense variants are damaging to BRSK2 structure and function. All nine variants are absent from large variant databases, and BRSK2 is, in general, relatively intolerant to protein-altering variation among humans. In all six probands for whom parents were available, the mutations were found to have arisen de novo. Five of these de novo variants were from cohorts with at least 400 sequenced probands; collectively, the cohorts span 3,429 probands, and the observed rate of de novo variation in these cohorts is significantly higher than the estimated background-mutation rate (p = 2.46 × 10$^{-6}$). We also find that exome sequencing provides lower coverage and appears less sensitive to rare variation in BRSK2 than does genome sequencing; this fact most likely reduces BRSK2's visibility in many clinical and research sequencing efforts. Altogether, our results implicate damaging variation in BRSK2 as a source of neurodevelopmental disease.

Published
2019

Catalog

Books, media, physical & digital resources
See catalog results