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1. ARF1-related disorder: phenotypic and molecular spectrum.

Author

de Sainte Agathe, Jean-Madeleine, Pode-Shakked, Ben, Naudion, Sophie, Michaud, Vincent, Arveiler, Benoit, Fergelot, Patricia, Delmas, Jean, Keren, Boris, Poirsier, Céline, Alkuraya, Fowzan, Tabarki, Brahim, Bend, Eric, Davis, Kellie, Bebin, Martina, Thompson, Michelle, Bryant, Emily, Wagner, Matias, Hannibal, Iris, Lenberg, Jerica, Krenn, Martin, Wigby, Kristen, Friedman, Jennifer, Iascone, Maria, Cereda, Anna, Miao, Térence, LeGuern, Eric, Sherr, Elliott, Caluseriu, Oana, Tidwell, Timothy, Bayrak-Toydemir, Pinar, Hagedorn, Caroline, Brugger, Melanie, Vill, Katharina, Morneau-Jacob, Francois-Dominique, Chung, Wendy, Weaver, Kathryn, Owens, Joshua, Husami, Ammar, Chaudhari, Bimal, Stone, Brandon, Burns, Katie, Li, Rachel, de Lange, Iris, Biehler, Margaux, Ginglinger, Emmanuelle, Gérard, Bénédicte, Stottmann, Rolf, Trimouille, Aurélien, and Argilli, Emanuela

Subjects
epilepsy, human genetics, sequence analysis, DNA, Humans, Brain, Genotype, Intellectual Disability, Microcephaly, Periventricular Nodular Heterotopia, Phenotype, Seizures
Abstract

PURPOSE: ARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1-related neurodevelopmental disorder. METHODS: We collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. RESULTS: De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. CONCLUSION: We confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.

Published
2023

2. Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles

Author

Bassani, Sissy, Chrast, Jacqueline, Ambrosini, Giovanna, Voisin, Norine, Schütz, Frédéric, Brusco, Alfredo, Sirchia, Fabio, Turban, Lydia, Schubert, Susanna, Abou Jamra, Rami, Schlump, Jan-Ulrich, DeMille, Desiree, Bayrak-Toydemir, Pinar, Nelson, Gary Rex, Wong, Kristen Nicole, Duncan, Laura, Mosera, Mackenzie, Gilissen, Christian, Vissers, Lisenka E. L. M., Pfundt, Rolph, Kersseboom, Rogier, Yttervik, Hilde, Hansen, Geir Åsmund Myge, Smeland, Marie Falkenberg, Butler, Kameryn M., Lyons, Michael J., Carvalho, Claudia M. B., Zhang, Chaofan, Lupski, James R., Potocki, Lorraine, Flores-Gallegos, Leticia, Morales-Toquero, Rodrigo, Petit, Florence, Yalcin, Binnaz, Tuttle, Annabelle, Elloumi, Houda Zghal, McCormick, Lane, Kukolich, Mary, Klaas, Oliver, Horvath, Judit, Scala, Marcello, Iacomino, Michele, Operto, Francesca, Zara, Federico, Writzl, Karin, Maver, Aleš, Haanpää, Maria K., Pohjola, Pia, Arikka, Harri, Kievit, Anneke J. A., Calandrini, Camilla, Iseli, Christian, Guex, Nicolas, and Reymond, Alexandre

Published
2024
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3. Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles

Author

Sissy Bassani, Jacqueline Chrast, Giovanna Ambrosini, Norine Voisin, Frédéric Schütz, Alfredo Brusco, Fabio Sirchia, Lydia Turban, Susanna Schubert, Rami Abou Jamra, Jan-Ulrich Schlump, Desiree DeMille, Pinar Bayrak-Toydemir, Gary Rex Nelson, Kristen Nicole Wong, Laura Duncan, Mackenzie Mosera, Christian Gilissen, Lisenka E. L. M. Vissers, Rolph Pfundt, Rogier Kersseboom, Hilde Yttervik, Geir Åsmund Myge Hansen, Marie Falkenberg Smeland, Kameryn M. Butler, Michael J. Lyons, Claudia M. B. Carvalho, Chaofan Zhang, James R. Lupski, Lorraine Potocki, Leticia Flores-Gallegos, Rodrigo Morales-Toquero, Florence Petit, Binnaz Yalcin, Annabelle Tuttle, Houda Zghal Elloumi, Lane McCormick, Mary Kukolich, Oliver Klaas, Judit Horvath, Marcello Scala, Michele Iacomino, Francesca Operto, Federico Zara, Karin Writzl, Aleš Maver, Maria K. Haanpää, Pia Pohjola, Harri Arikka, Anneke J. A. Kievit, Camilla Calandrini, Christian Iseli, Nicolas Guex, and Alexandre Reymond

Subjects
Mesomelic dysplasia, Horseshoe kidney, Intellectual disability, Transcriptome, Zebrafish model, Medicine, Genetics, QH426-470
Abstract

Abstract Background We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects. Methods Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. Results We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.

Published
2024
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4. Endocannabinoid dysfunction in neurological disease: neuro-ocular DAGLA-related syndrome (NODRS)

Author

Bainbridge, Matthew N, Mazumder, Aloran, Ogasawara, Daisuke, Jamra, Rami Abou, Bernard, Geneviève, Bertini, Enrico, Burglen, Lydie, Cope, Heidi, Crawford, Ali, Derksen, Alexa, Dure, Leon, Gantz, Emily, Koch-Hogrebe, Margarete, Hurst, Anna CE, Mahida, Sonal, Marshall, Paige, Micalizzi, Alessia, Novelli, Antonio, Peng, Hongfan, Medicine, Rady Children's Institute for Genomic, Rodriguez, Diana, Robbins, Shira L, Rutledge, S Lane, Scalise, Roberta, Schließke, Sophia, Shashi, Vandana, Srivastava, Siddharth, Thiffault, Isabella, Topol, Sarah, Acosta, Maria T, Adam, Margaret, Adams, David R, Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A, Azamian, Mahshid S, Bacino, Carlos A, Bademci, Guney, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H, Behrens, Edward, Bejerano, Gill, Bennet, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A, Berry, Gerard T, Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C, Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A, Burrage, Lindsay C, Butte, Manish J, Byers, Peter, Byrd, William E, Carey, John, Carrasquillo, Olveen, Cassini, Thomas, Chang, Ta Chen Peter, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D, Coakley, Terra R, Cobban, Laurel A, Cogan, Joy D, Coggins, Matthew, Cole, F Sessions, Colley, Heather A, Cooper, Cynthia M, Craigen, William J, Crouse, Andrew B, Cunningham, Michael, D’Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G, Deardorff, Matthew, Dell’Angelica, Esteban C, Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L, Douine, Emilie D, Duncan, Laura, and Earl, Dawn

Subjects
Biotechnology, Brain Disorders, Genetics, Neurosciences, Clinical Research, Rare Diseases, Eye Disease and Disorders of Vision, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Neurological, Humans, Child, Endocannabinoids, Phenotype, Nervous System Diseases, Heterozygote, Syndrome, Mutant Proteins, endocannabinoid, episodic ataxia, paroxysmal tonic upgaze, nystagmus, developmental delay, Rady Children's Institute for Genomic Medicine, Undiagnosed Disease Network, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The endocannabinoid system is a highly conserved and ubiquitous signalling pathway with broad-ranging effects. Despite critical pathway functions, gene variants have not previously been conclusively linked to human disease. We identified nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. All children displayed paroxysms of nystagmus or eye deviation accompanied by compensatory head posture and worsened incoordination most frequently after waking. RNA sequencing showed clear expression of the truncated transcript and no differences were found between mutant and wild-type DAGLA activity. Immunofluorescence staining of patient-derived fibroblasts and HEK cells expressing the mutant protein showed distinct perinuclear aggregation not detected in control samples. This report establishes truncating variants in the last DAGLA exon as the cause of a unique paediatric syndrome. Because enzymatic activity was preserved, the observed mislocalization of the truncated protein may account for the observed phenotype. Potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect. To our knowledge, this is the first report directly linking an endocannabinoid system component with human genetic disease and sets the stage for potential future therapeutic avenues.

Published
2022

5. A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder

Author

Shankar, Suma P, Grimsrud, Kristin, Lanoue, Louise, Egense, Alena, Willis, Brandon, Hörberg, Johanna, AlAbdi, Mayer, Klaus, Ütkür, Koray, Monaghan, Kristin G, Krier, Joel, Stoler, Joan, Alnemer, Maha, Shankar, Prabhu R, Schaffrath, Raffael, Alkuraya, Fowzan S, Brinkmann, Ulrich, Eriksson, Leif A, Lloyd, Kent, Rauen, Katherine A, Network, Undiagnosed Diseases, Acosta, Maria T, Adam, Margaret, Adams, David R, Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A, Azamian, Mahshid S, Bacino, Carlos A, Bademci, Guney, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H, Behrens, Edward, Bejerano, Gill, Bennet, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A, Berry, Gerard T, Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C, Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A, Burrage, Lindsay C, Butte, Manish J, Byers, Peter, Byrd, William E, Carey, John, Carrasquillo, Olveen, Cassini, Thomas, Chang, Ta Chen Peter, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D, Coakley, Terra R, Cobban, Laurel A, Cogan, Joy D, Coggins, Matthew, Cole, F Sessions, Colley, Heather A, Cooper, Cynthia M, Cope, Heidi, Craigen, William J, Crouse, Andrew B, Cunningham, Michael, D'Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G, Deardorff, Matthew, Dell'Angelica, Esteban C, Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L, Douine, Emilie D, Duncan, Laura, Earl, Dawn, Eckstein, David J, Emrick, Lisa T, Eng, Christine M, Esteves, Cecilia, Falk, Marni, Fernandez, Liliana, Fieg, Elizabeth L, and Fisher, Paul G

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Pediatric, Human Genome, 2.1 Biological and endogenous factors, Adenosine Diphosphate, Animals, Histidine, Humans, Methyltransferases, Mice, Mice, Inbred C57BL, Neurodevelopmental Disorders, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Syndrome, Nonverbal neurodevelopment delays, Novel gene discovery, Precision animal modeling, Precision genomics, Translational genetics, Undiagnosed Diseases Network, Clinical Sciences, Genetics & Heredity
Abstract

PurposeDiphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs).MethodsMolecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants.ResultsDPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2.ConclusionWe provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.

Published
2022

6. Clinical application of a scale to assess genomic healthcare empowerment (GEmS): Process and illustrative case examples

Author

McConkie‐Rosell, Allyn, Schoch, Kelly, Sullivan, Jennifer, Spillmann, Rebecca C, Cope, Heidi, Tan, Queenie K‐G, Palmer, Christina GS, Hooper, Stephen R, Shashi, Vandana, Acosta, Maria T, Adam, Margaret, Adams, David R, Agrawal, Pankaj B, Alejandro, Mercedes E, Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A, Azamian, Mahshid S, Bacino, Carlos A, Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak‐Toydemir, Pinar, Beck, Anita, Beggs, Alan H, Behrens, Edward, Bejerano, Gill, Bennet, Jimmy, Berg‐Rood, Beverly, Bernstein, Jonathan A, Berry, Gerard T, Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonnenmann, Carsten, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C, Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A, Burrage, Lindsay C, Butte, Manish J, Byers, Peter, Byrd, William E, Carey, John, Carrasquillo, Olveen, Chang, Ta Chen Peter, Chanprasert, Sirisak, Chao, Hsiao‐Tuan, Clark, Gary D, Coakley, Terra R, Cobban, Laurel A, Cogan, Joy D, Coggins, Matthew, Sessions Cole, F, Colley, Heather A, Cooper, Cynthia M, Craigen, William J, Crouse, Andrew B, Cunningham, Michael, D'Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davids, Mariska, Dayal, Jyoti G, Deardorff, Matthew, Dell'Angelica, Esteban C, Dhar, Shweta U, Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Douine, Emilie D, Draper, David D, Duncan, Laura, Earl, Dawn, Eckstein, David J, Emrick, Lisa T, Eng, Christine M, Esteves, Cecilia, Estwick, Tyra, Falk, Marni, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L, Findley, Laurie C, Fisher, Paul G, Fogel, Brent L, Forghani, Irman, Fresard, Laure, Gahl, William A, Glass, Ian, and Godfrey, Rena A

Subjects
Pediatric, Biotechnology, Human Genome, Clinical Research, Genetics, Good Health and Well Being, Child, Delivery of Health Care, Family, Genomics, Humans, Parents, Exome Sequencing, exome and genomic sequencing, undiagnosed disorders, healthcare empowerment, genetic counseling, parental perspectives, rare disorders, Undiagnosed Disease Network, Clinical Sciences, Genetics & Heredity
Abstract

The Genome Empowerment Scale (GEmS), developed as a research tool, assesses perspectives of parents of children with undiagnosed disorders about to undergo exome or genome sequencing related to the process of empowerment. We defined genomic healthcare empowerment as follows: perceived ability to understand and seek new information related to the genomic sequencing, manage emotions related to the diagnostic process and outcomes, and utilize genomic sequencing information to the betterment of the individual/child and family. The GEmS consists of four scales, two are primarily emotion-focused (Meaning of a Diagnosis, and Emotional Management of the Process) and two are action-oriented (Seeking Information and Support, and Implications and Planning). The purpose of this research was to provide a strategy for interpreting results from the GEmS and present illustrative cases. These illustrations should serve to facilitate use of the GEmS in the clinical and research arena, particularly with respect to guiding genetic counseling processes for parents of children with undiagnosed conditions.

Published
2022

7. P398: A rare report of a child with mosaic trisomy 4

Author

Lauren Bartik, Elena Repnikova, Eric Rush, Jennifer Roberts, Erin Baldwin, John Carey, Lorenzo Botto, John O'Shea, Ting Wen, Pinar Bayrak-Toydemir, Rong Mao, Undiagnosed Diseases Network, and Bonnie Sullivan

Subjects
Genetics, QH426-470, Medicine
Published
2024
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8. O20: Beyond the genome: RNA sequencing resolves unique diagnostic challenges

Author

Robert Lewis, Makenzie Fulmer, Jian Zhao, Lucilla Pizzo, Ting Wen, John O'Shea, Thomas Nicholas, Steven Boyden, David Viskochil, Nicola Longo, Ashley Andrews, Erin Baldwin, Matt Velinder, Russell Butterfield, Karin Dent, Kourtney Santucci, Austin Larson, Rong Mao, Lorenzo Botto, and Pinar Bayrak-Toydemir

Subjects
Genetics, QH426-470, Medicine
Published
2024
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9. A direct comparison of next generation sequencing enrichment methods using an aortopathy gene panel- clinical diagnostics perspective

Author

Wooderchak-Donahue Whitney L, O’Fallon Brendan, Furtado Larissa V, Durtschi Jacob D, Plant Parker, Ridge Perry G, Rope Alan F, Yetman Angela T, and Bayrak-Toydemir Pinar

Subjects
Aortopathy, Hybridization capture, Marfan syndrome, Next generation sequencing (NGS), Target enrichment, Emulsion PCR, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Aortopathies are a group of disorders characterized by aneurysms, dilation, and tortuosity of the aorta. Because of the phenotypic overlap and genetic heterogeneity of diseases featuring aortopathy, molecular testing is often required for timely and correct diagnosis of affected individuals. In this setting next generation sequencing (NGS) offers several advantages over traditional molecular techniques. Methods The purpose of our study was to compare NGS enrichment methods for a clinical assay targeting the nine genes known to be associated with aortopathy. RainDance emulsion PCR and SureSelect RNA-bait hybridization capture enrichment methods were directly compared by enriching DNA from eight samples. Enriched samples were barcoded, pooled, and sequenced on the Illumina HiSeq2000 platform. Depth of coverage, consistency of coverage across samples, and the overlap of variants identified were assessed. This data was also compared to whole-exome sequencing data from ten individuals. Results Read depth was greater and less variable among samples that had been enriched using the RNA-bait hybridization capture enrichment method. In addition, samples enriched by hybridization capture had fewer exons with mean coverage less than 10, reducing the need for followup Sanger sequencing. Variants sets produced were 77% concordant, with both techniques yielding similar numbers of discordant variants. Conclusions When comparing the design flexibility, performance, and cost of the targeted enrichment methods to whole-exome sequencing, the RNA-bait hybridization capture enrichment gene panel offers the better solution for interrogating the aortopathy genes in a clinical laboratory setting.

Published
2012
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10. 5'UTR mutations of ENG cause hereditary hemorrhagic telangiectasia

Author

Damjanovich Kristy, Langa Carmen, Blanco Francisco J, McDonald Jamie, Botella Luisa M, Bernabeu Carmelo, Wooderchak-Donahue Whitney, Stevenson David A, and Bayrak-Toydemir Pinar

Subjects
5'UTR region, ENG, +T%22">c.-127C > T, +A%22">c.-9G > A, homozygous, Medicine
Abstract

Abstract Background Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by epistaxis, arteriovenous malformations, and telangiectases. The majority of the patients have a mutation in the coding region of the activin A receptor type II-like 1 (ACVRL1) or Endoglin (ENG) gene. However, in approximately 15% of cases, sequencing analysis and deletion/duplication testing fail to identify mutations in the coding regions of these genes. Knowing its vital role in transcription and translation control, we were prompted to investigate the 5'untranslated region (UTR) of ENG. Methods and Results We sequenced the 5'UTR of ENG for 154 HHT patients without mutations in ENG or ACVRL1 coding regions. We found a mutation (c.-127C > T), which is predicted to affect translation initiation and alter the reading frame of endoglin. This mutation was found in a family with linkage to the ENG, as well as in three other patients, one of which had an affected sibling with the same mutation. In vitro expression studies showed that a construct with the c.-127C > T mutation alters the translation and decreases the level of the endoglin protein. In addition, a c.-9G > A mutation was found in three patients, one of whom was homozygous for this mutation. Expression studies showed decreased protein levels suggesting that the c.-9G > A is a hypomorphic mutation. Conclusions Our results emphasize the need for the inclusion of the 5'UTR region of ENG in clinical testing for HHT.

Published
2011
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11. Characterization of large genomic deletions in the FBN1 gene using multiplex ligation-dependent probe amplification

Author

Lewis Tracey, Yetman Angela T, Rope Alan F, Wooderchak-Donahue Whitney, Furtado Larissa V, Plant Parker, and Bayrak-Toydemir Pinar

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Connective tissue diseases characterized by aortic aneurysm, such as Marfan syndrome, Loeys-Dietz syndrome and Ehlers Danlos syndrome type IV are heterogeneous and despite overlapping phenotypes, the natural history, clinical manifestations and interventional course for each diagnosis can be quite unique. The majority of mutations involved in the etiology of these disorders are missense and nonsense mutations. However, large deletions and duplications undetected by sequencing may be implicated in their pathogenesis, and may explain the apparent lack of genotype-phenotype correlation in a subset of patients. The objective of this study was to search for large pathogenic deletions and/or duplications in the FBN1, TGFβR1, and TGFβR2 genes using multiplex-ligation dependent probe amplification (MLPA) in patients with aortopathy, in whom no mutations in the FBN1, TGFβR1, and TGFβR2 genes were identified by sequencing. Methods The study included 14 patients from 11 unrelated families with aortic aneurysm. Of those, six patients (including 3 first-degree relatives), fulfilled the revised Ghent criteria for Marfan syndrome, and eight had predominantly aortic aneurysm/dilatation with variable skeletal and craniofacial involvement. MLPA for FBN1, TGFβR1, and TGFβR2 was carried out in all patients. A 385 K chromosome 15 specific array was used in two patients with a deletion of the entire FBN1 in order to define its size and boundaries. Results We identified two novel large deletions in the FBN1 gene in four patients of two unrelated families who met clinical diagnostic criteria for Marfan syndrome. One patient was found to have a FBN1 deletion encompassing exons 1-5. The other three patients had a 542 Kb deletion spanning the whole FBN1 gene and five additional genes (SLC24A5, MYEF2, CTXN2, SLC12A1, DUT) in the chromosome 15. Conclusions Our findings expand the number of large FBN1 deletions, and emphasize the importance of screening for large genomic deletions in connective tissue disorders featuring aortopathies, especially for those with classic Marfan phenotype.

Published
2011
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13. De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects

Author

Accogli, Andrea, Calabretta, Sara, St-Onge, Judith, Boudrahem-Addour, Nassima, Dionne-Laporte, Alexandre, Joset, Pascal, Azzarello-Burri, Silvia, Rauch, Anita, Krier, Joel, Fieg, Elizabeth, Pallais, Juan C, Network, Undiagnosed Diseases, Acosta, Maria T, Adams, David R, Agrawal, Pankaj, Alejandro, Mercedes E, Allard, Patrick, Alvey, Justin, Andrews, Ashley, Ashley, Euan A, Azamian, Mahshid S, Bacino, Carlos A, Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Barbouth, Deborah, Batzli, Gabriel F, Bayrak-Toydemir, Pinar, Beggs, Alan H, Bejerano, Gill, Bellen, Hugo J, Bernstein, Jonathan A, Berry, Gerard T, Bican, Anna, Bick, David P, Birch, Camille L, Bivona, Stephanie, Bohnsack, John, Bonnenmann, Carsten, Bonner, Devon, Boone, Braden E, Bostwick, Bret L, Botto, Lorenzo, Briere, Lauren C, Brokamp, Elly, Brown, Donna M, Brush, Matthew, Burke, Elizabeth A, Burrage, Lindsay C, Butte, Manish J, Carey, John, Carrasquillo, Olveen, Chang, Ta Chen Peter, Chao, Hsiao-Tuan, Clark, Gary D, Coakley, Terra R, Cobban, Laurel A, Cogan, Joy D, Cole, F Sessions, Colley, Heather A, Cooper, Cynthia M, Cope, Heidi, Craigen, William J, D’Souza, Precilla, Dasari, Surendra, Davids, Mariska, Dayal, Jyoti G, Dell’Angelica, Esteban C, Dhar, Shweta U, Dorrani, Naghmeh, Dorset, Daniel C, Douine, Emilie D, Draper, David D, Duncan, Laura, Eckstein, David J, Emrick, Lisa T, Eng, Christine M, Esteves, Cecilia, Estwick, Tyra, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L, Fisher, Paul G, Fogel, Brent L, Forghani, Irman, Fresard, Laure, Gahl, William A, Godfrey, Rena A, Goldman, Alica M, Goldstein, David B, Gourdine, Jean-Philippe F, Grajewski, Alana, Groden, Catherine A, Gropman, Andrea L, Haendel, Melissa, Hamid, Rizwan, Hanchard, Neil A, and Hayes, Nichole

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Genetics, Biological Sciences, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Axons, Cadherins, Corpus Callosum, Eye, Frameshift Mutation, Genitalia, Heart Defects, Congenital, Heterozygote, Humans, Neurodevelopmental Disorders, Undiagnosed Diseases Network, ACOG, CDH2, N-cadherin, cardiac defects, cell-cell adhesion, corpus callosum, eye defects, genital defects, intellectual disability, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).

Published
2019

15. P243: The Utah NeoSeq Project: Developing and implementing genomic sequencing in acute neonatal care

Author

Sabrina Malone-Jenkins, Brian Shayota, Chelsea Solorzano, Rachel Palmquist, Steven Boyden, Barry Moore, Thomas Nicholas, Rong Mao, Pinar Bayrak-Toydemir, Katherine Noble, Andrew Farrell, Edgar Hernandez, Shawn Rynearson, Carson Holt, Alistair Ward, Najla Al-Sweel, Jian Zhao, Makenzie Fulmer, Lucilla Pizzo, Ting Wen, John O'Shea, Robert Lewis, Hayley Reynolds, Eric Fredrickson, Kelsey Nicholson, David Pattison, Hunter Best, Luca Brunelli, Mark Yandell, Gabor Marth, Aaron Quinlan, John Carey, Martin Tristani-Firouzi, and Joshua Bonkowsky

Subjects
Genetics, QH426-470, Medicine
Published
2023
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16. O31: Risk allele evidence curation, classification, and reporting: Recommendations from the ClinGen Low Penetrance/Risk Allele Working Group

Author

Matthew Lebo, Marcie Steeves, Katherine Benson, Laura Conlin, Mythily Ganapathi, Vaidehi Jobanputra, Minjie Luo, Deqiong Ma, Kelly McGoldrick, Blake Palculict, Heidi Rehm, Panagiotis Sergouniotis, Samantha Schilit, Pinar Bayrak-Toydemir, Tatiana Tvrdik, Nicholas Watkins, Lauren Zec, Wenying Zhang Zhang, and Ryan Schmidt

Subjects
Genetics, QH426-470, Medicine
Published
2023
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19. P516: RNASeq analysis identifies the pathogenicity of inherited synonymous splice-region variant in NEB, confirming a diagnosis of neonatal nemaline myopathy 2

Author

Barry Moore, Thomas Nicholas, Rong Mao, Brian Shayota, Steven Boyden, Chelsea Solorzano, Rachel Palmquist, Pinar Bayrak-Toydemir, Katherine Noble, Andrew Farrell, Edgar Hernandez, Shawn Rynearson, Carson Holt, Alistair Ward, Eric Fredrickson, Kelsey Nicholson, David Pattison, Jian Zhao, Makenzie Fulmer, Lucilla Pizzo, Ting Wen, John O'Shea, Robert Lewis, Hayley Reynolds, Betsy Ostrander, Hunter Best, Luca Brunelli, Mark Yandell, Gabor Marth, Aaron Quinlan, John Carey, Martin Tristani-Firouzi, Joshua Bonkowsky, and Sabrina Malone-Jenkins

Subjects
Genetics, QH426-470, Medicine
Published
2023
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22. P585: Rapid genome sequencing identifies a de novo SNAP25 variant for neonatal congenital myasthenic syndrome

Author

Ting Wen, Hayley Reynolds, Andrew Farrell, Barry Moore, Steven Boyden, Thomas Nicholas, Shawn Rynearson, Carson Holt, Christine Miller, Katherine Noble, Dawn Bentley, Rachel Palmquist, Betsy Ostrander, Stephanie Manberg, Joshua Bonkowsky, Brian Shayota, Sabrina Malone-Jenkins, Pinar Bayrak-Toydemir, and Rong Mao

Subjects
Genetics, QH426-470, Medicine
Published
2023
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24. P665: Recommendations for the improvement of diagnostic yields in rare disease cases through the integration of structural variants into analytical pipelines

Author

Thomas Nicholas, Andrew Farrell, Shawn Rynearson, Carson Holt, Steven Boyden, Barry Moore, Najla Al-Sweel, Christine Miller, Lucilla Pizzo, Chelsea Solorzano, Rachel Palmquist, Ashley Andrews, Rong Mao, Pinar Bayrak-Toydemir, Eric Fredrickson, Katherine Noble, Brian Shayota, Joshua Bonkowsky, John Carey, Sabrina Malone-Jenkins, Lorenzo Botto, and Aaron Quinlan

Subjects
Genetics, QH426-470, Medicine
Published
2023
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25. Inactivating mutations in Drosha mediate vascular abnormalities similar to hereditary hemorrhagic telangiectasia

Author

Jiang, Xuan, Wooderchak-Donahue, Whitney L, McDonald, Jamie, Ghatpande, Prajakta, Baalbaki, Mai, Sandoval, Melissa, Hart, Daniel, Clay, Hilary, Coughlin, Shaun, Lagna, Giorgio, Bayrak-Toydemir, Pinar, and Hata, Akiko

Subjects
Biochemistry and Cell Biology, Biological Sciences, Hematology, Genetics, Rare Diseases, Biotechnology, Underpinning research, 1.1 Normal biological development and functioning, Animals, Case-Control Studies, Cells, Cultured, Child, Cohort Studies, Endothelium, Vascular, Female, Gene Expression Regulation, Humans, Male, Mice, Mice, Knockout, Morphogenesis, Mutation, Neovascularization, Pathologic, Pedigree, Phenotype, Ribonuclease III, Signal Transduction, Telangiectasia, Hereditary Hemorrhagic, Zebrafish, Biochemistry and cell biology
Abstract

The transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) family of cytokines critically regulates vascular morphogenesis and homeostasis. Impairment of TGF-β or BMP signaling leads to heritable vascular disorders, including hereditary hemorrhagic telangiectasia (HHT). Drosha, a key enzyme for microRNA (miRNA) biogenesis, also regulates the TGF-β and BMP pathway through interaction with Smads and their joint control of gene expression through miRNAs. We report that mice lacking Drosha in the vascular endothelium developed a vascular phenotype resembling HHT that included dilated and disorganized vasculature, arteriovenous fistulae, and hemorrhages. Exome sequencing of HHT patients who lacked known pathogenic mutations revealed an overrepresentation of rare nonsynonymous variants of DROSHA Two of these DROSHA variants (P100L and R279L) did not interact with Smads and were partially catalytically active. In zebrafish, expression of these mutants or morpholino-directed knockdown of Drosha resulted in angiogenesis defects and abnormal vascular permeability. Together, our studies point to an essential role of Drosha in vascular development and the maintenance of vascular integrity, and reveal a previously unappreciated link between Drosha dysfunction and HHT.

Published
2018

26. Comprehensive variant calling from whole‐genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia

Author

Thomas J. Nicholas, Najla Al‐Sweel, Andrew Farrell, Rong Mao, Pinar Bayrak‐Toydemir, Christine E. Miller, Dawn Bentley, Rachel Palmquist, Barry Moore, Edgar J. Hernandez, Michael J. Cormier, Eric Fredrickson, Katherine Noble, Shawn Rynearson, Carson Holt, Mary Anne Karren, Joshua L. Bonkowsky, Martin Tristani‐Firouzi, Mark Yandell, Gabor Marth, Aaron R. Quinlan, Luca Brunelli, Reha M. Toydemir, Brian J. Shayota, John C. Carey, Steven E. Boyden, and Sabrina Malone Jenkins

Subjects
Genetics, QH426-470
Abstract

Abstract Background Genetic disorders contribute to significant morbidity and mortality in critically ill newborns. Despite advances in genome sequencing technologies, a majority of neonatal cases remain unsolved. Complex structural variants (SVs) often elude conventional genome sequencing variant calling pipelines and will explain a portion of these unsolved cases. Methods As part of the Utah NeoSeq project, we used a research‐based, rapid whole‐genome sequencing (WGS) protocol to investigate the genomic etiology for a newborn with a left‐sided congenital diaphragmatic hernia (CDH) and cardiac malformations, whose mother also had a history of CDH and atrial septal defect. Results Using both a novel, alignment‐free and traditional alignment‐based variant callers, we identified a maternally inherited complex SV on chromosome 8, consisting of an inversion flanked by deletions. This complex inversion, further confirmed using orthogonal molecular techniques, disrupts the ZFPM2 gene, which is associated with both CDH and various congenital heart defects. Conclusions Our results demonstrate that complex structural events, which often are unidentifiable or not reported by clinically validated testing procedures, can be discovered and accurately characterized with conventional, short‐read sequencing and underscore the utility of WGS as a first‐line diagnostic tool.

Published
2022
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27. The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway

Author

Stevenson, David A, Schill, Lisa, Schoyer, Lisa, Andresen, Brage S, Bakker, Annette, Bayrak-Toydemir, Pinar, Burkitt-Wright, Emma, Chatfield, Kathryn, Elefteriou, Florent, Elgersma, Ype, Fisher, Michael J, Franz, David, Gelb, Bruce D, Goriely, Anne, Gripp, Karen W, Hardan, Antonio Y, Keppler-Noreuil, Kim M, Kerr, Bronwyn, Korf, Bruce, Leoni, Chiara, McCormick, Frank, Plotkin, Scott R, Rauen, Katherine A, Reilly, Karlyne, Roberts, Amy, Sandler, Abby, Siegel, Dawn, Walsh, Karin, and Widemann, Brigitte C

Subjects
Biological Sciences, Genetics, Congenital Structural Anomalies, Neurosciences, Rare Diseases, Pediatric, Congenital, Capital Financing, Clinical Trials as Topic, Family, Genetic Diseases, Inborn, Humans, Intersectoral Collaboration, Mitogen-Activated Protein Kinases, Signal Transduction, ras Proteins, RASopathy, Ras, MAPK, cancer, rare disorders, clinical trials, experimental models, Ras/MAPK, Clinical Sciences, Clinical sciences
Abstract

The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. © 2016 Wiley Periodicals, Inc.

Published
2016

30. Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)?

Author

Wooderchak-Donahue, Whitney L., Akay, Gulsen, Whitehead, Kevin, Briggs, Eric, Stevenson, David A., O’Fallon, Brendan, Velinder, Matthew, Farrell, Andrew, Shen, Wei, Bedoukian, Emma, Skrabann, Cara M., Antaya, Richard J., Henderson, Kate, Pollak, Jeffrey, Treat, James, Day, Ronald, Jacher, Joseph E., Hannibal, Mark, Bontempo, Kelly, Marth, Gabor, Bayrak-Toydemir, Pinar, and McDonald, Jamie

Published
2019
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31. Misattributed parentage as an unanticipated finding during exome/genome sequencing: current clinical laboratory practices and an opportunity for standardization

Author

Eno, Celeste, Bayrak-Toydemir, Pinar, Bean, Lora, Braxton, Alicia, Chao, Elizabeth C., El-Khechen, Dima, Esplin, Edward D., Friedman, Bethany, Hagman, Kelly D. Farwell, Hambuch, Tina, Hernandez, Amy, Juusola, Jane, Londre, Gina, Machado, Jerry, Mao, Rong, Mighion, Lindsey, Rehm, Heidi L., Ward, Patricia, and Deignan, Joshua L.

Published
2019
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34. Slice Testing—Considerations from Ordering to Reporting

Author

SoRelle, Jeffrey A., Funke, Birgit H., Eno, Celeste C., Ji, Jianling, Santani, Avni, Bayrak-Toydemir, Pinar, Wachsmann, Megan, Wain, Karen E., and Mao, Rong

Abstract

As the number of genes associated with various germline disorders continues to grow, it is becoming more difficult for clinical laboratories to maintain separate assays for interrogating disease-focused gene panels. One solution to this challenge is termed slice testing, where capture backbone is used to analyze data specific to a set of genes, and for this article, we will focus on exome. A key advantage to this strategy is greater flexibility by adding genes as they become associated with disease or the ability to accommodate specific provider requests. Here, we provide expert consensus recommendations and results from an Association for Molecular Pathology–sponsored survey of clinical laboratories performing exome sequencing to compare a slice testing approach with traditional static gene panels and comprehensive exome analysis. We explore specific considerations for slices, including gene selection, analytic performance, coverage, quality, and interpretation. Our goal is to provide comprehensive guidance for clinical laboratories interested in designing and using slice tests as a diagnostic.

Published
2024
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38. The Shunt of It

Author

Scarpato, Brittany M., McDonald, Jamie, Bayrak-Toydemir, Pinar, Elliott, C. Gregory, Cahill, Barbara C., Emerson, Lyska L., and Keenan, Lynn M.

Abstract

Pulmonary arteriovenous malformations (PAVMs) are rare and most often identified in patients with hereditary hemorrhagic telangiectasia (HHT). We describe a patient with severe hypoxemia and orthodeoxia with imaging findings consistent with PAVMs. Resected lung pathologic findings confirmed the presence of numerous microscopic vascular abnormalities within the right lower lobe that was consistent with diffuse pulmonary arteriovenous shunts. Family history was negative for HHT but was positive for pulmonary arterial hypertension (PAH) in two second-degree relatives. A vascular malformation gene panel was negative for genes that commonly are associated with HHT but identified a pathogenic variant in the gene encoding bone morphogenetic protein receptor-2 (BMPR2p.Cys123∗). Pathogenic variants in BMPR2are a well-known cause of hereditary PAH; there have been several reports to date of patients with PAVMs and PAH. However, this is the first patient to be reported with a pathogenic variant in BMPR2to have PAVMs in isolation.

Published
2023
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39. Contributors

Author

Abbasi, S., primary, Adolphi, N.L., additional, Aikawa, E., additional, Akbar, H., additional, Akilesh, S., additional, Aladjem, M.I., additional, Allocca, M., additional, Alpini, G., additional, Alroy, J., additional, Altman, B.J., additional, Andujar, P., additional, Antonello, Z.A., additional, Antsiferova, M., additional, Apica, B.S., additional, Ariel, I., additional, Aronow, B.J., additional, Ashley, J.W., additional, Badell, I.R., additional, Bagg, A., additional, Bajaj, M., additional, Banerjee, S., additional, Barbieri, J.S., additional, Bardes, E.E., additional, Barisoni, L., additional, Barletta, J.A., additional, Baskin, D.G., additional, Bastarrachea, R.A., additional, Bayat, A., additional, Bayrak-Toydemir, P., additional, Beck, A.H., additional, Beebe, D.C., additional, Beltran, H., additional, Benichou, G., additional, Bergman, M., additional, Bernard, S.A., additional, Bernardi, P., additional, Best, D.H., additional, Blair, H.C., additional, Bonaldo, P., additional, Bondy, J., additional, Bosman, F.T., additional, Bouma, B.E., additional, Brandi, M.L., additional, Bresler, S.C., additional, Brewer, M.T., additional, Britto, C.J., additional, Brock, J.E., additional, Brosens, L.A.A., additional, Budge, H., additional, Burd, E.M., additional, Burness, M.L., additional, Bushnell, T., additional, Byrd, J., additional, Calderone, A., additional, Campbell, M.J., additional, Cao, D., additional, Capell, W., additional, Cardigan, R., additional, Carey, P.M., additional, Carneiro, F., additional, Carp, S.A., additional, Carter, A.M., additional, Cascio, M.J., additional, Castellani, R.J., additional, Castellanos, J., additional, Caviglia, J.M., additional, Cecconi, F., additional, Chamarthy, S., additional, Chamma, E., additional, Chang, A., additional, Chang, A.Y., additional, Chang, N.C., additional, Chapman, D.G., additional, Charles, A.K., additional, Chen, D., additional, Chen, D.F., additional, Chen, P., additional, Cheng, J., additional, Chernock, R.D., additional, Cheruvu, S., additional, Chiang, J., additional, Childs, G.V., additional, Cho, Y.-B., additional, Choi, A.M.K., additional, Choi, J.K., additional, Cipriani, N.A., additional, Cleary, J.O.S.H., additional, Clementi, E., additional, Clines, G.A., additional, Cohen, M.L., additional, Coleman, W.B., additional, Coletta, D.K., additional, Collie, A.M.B., additional, Cooling, L., additional, Coron, E., additional, Côté, D., additional, Coussens, L.M., additional, Crielaard, B.J., additional, Cron, R.Q., additional, Crum, C.P., additional, Cruz, N.M., additional, Dairkee, S.H., additional, Daly, C.A., additional, Dang, C.V., additional, Danila, M.I., additional, Daradich, A., additional, Darnell, C.M., additional, Dartt, D.A., additional, Das, A., additional, D’Asta, F., additional, DeFronzo, R., additional, De Hertogh, G., additional, Dela Cruz, C.S., additional, de la Cruz-Merino, L., additional, De Palma, C., additional, Demetris, A.J., additional, DeMorrow, S., additional, Denechaud, P.-D., additional, Di Carli, M.F., additional, DiCarlo, E.F., additional, Dikic, I., additional, Dimberg, A., additional, Dowell, M.L., additional, Doyle, L.A., additional, Drachenberg, C.B., additional, Driskell, E., additional, Duda, D.G., additional, Duker, J., additional, Dyck, J.R.B., additional, Ecker, C., additional, Elifritz, J.M., additional, Elsheikh, T.M., additional, Ensari, A., additional, Ernst, L.M., additional, Esch, K.J., additional, Fajas-Coll, L., additional, Fang, Q., additional, Farhat, N.A., additional, Farshid, G., additional, Faye-Petersen, O.M., additional, Fehlings, M.G., additional, Fend, F., additional, Feng, X., additional, Fernandes, H., additional, Fernandez-Checa, J.C., additional, Ferreira, B.P., additional, Fidler, I.J., additional, Finn, J.A., additional, Fischer, A., additional, Fishbein, M.C., additional, Fleit, H.B., additional, Flomenbaum, M., additional, Folkins, A., additional, Francis, H., additional, Frank, K.M., additional, Frevert, C.W., additional, Frias, A.E., additional, Friedman, J.R., additional, Fukumura, D., additional, Furie, M.B., additional, Gaffo, A.L., additional, Galateau-Sallé, F., additional, Gallegos-Cabriales, E.C., additional, Gandhi, C.R., additional, Gannon, M., additional, García-Moliner, M.L., additional, Gardner, J.M., additional, Gasper, C.A., additional, Gaulard, P., additional, Gaut, J.P., additional, Gavia-García, G., additional, Gerrard, C., additional, Ghosh, A.P., additional, Giersch, A.B.S, additional, Gilbert, S.R., additional, Gill, J.R., additional, Giusti, F., additional, Glorioso, J.M., additional, González-Torres, M.C., additional, Goolsby, C.L., additional, Gora, M.J., additional, Gordon, I.O., additional, Gotlieb, A.I., additional, Gouw, A.M., additional, Goyal, A., additional, Grégoire, M., additional, Graham, B.B., additional, Granger, D.N., additional, Greene, A.K., additional, Greenlee, J.J., additional, Griffiths, R., additional, Guimarães, A.R., additional, Gulati, M., additional, Gullet, A., additional, Gupta, S., additional, Haider, N.B., additional, Halushka, M.K., additional, Hambuch, T.M., additional, Hamza, S.M., additional, Han, Y., additional, Hansen, W.P., additional, Hard, R., additional, Harris, B.T., additional, Harris, J.E., additional, Hartnett, M.E., additional, Hasserjian, R.P., additional, Hatch, G.M., additional, Hefti, M.M., additional, Heller, D.S., additional, Hemminger, J.A., additional, Hendrickson, J.E., additional, Henley, K.D., additional, Herzog, E., additional, Hess, J.R., additional, Hill, C.E., additional, Hipp, J., additional, Hobbs, R., additional, Höller, D., additional, Hodges, R.R., additional, Homer, R.J., additional, Horowitz, N., additional, Hsi, E.D., additional, Hsieh, A.L., additional, Hunt, J.M., additional, Hure, S., additional, Husain, A.N., additional, Hussey, S., additional, Hutcheson, J.D., additional, Hutson, R.M., additional, Illescas-Vacas, A., additional, Irvin, C.G., additional, Jaffer, F.A., additional, Jäger, R., additional, Jain, R.K., additional, Jain, S., additional, James, J., additional, Jansen, M., additional, Jarzembowski, J.A., additional, Jaurand, M.-C., additional, Jean, D., additional, Jegga, A.G., additional, Jellinger, K.A., additional, Jen, K.-Y., additional, Jo, V.Y., additional, Johnson, B., additional, Jones, R.L., additional, Kalfa, T.A., additional, Kamionek, M., additional, Kang, D., additional, Kantari, C., additional, Kantor, P.F., additional, Kanzaki, G., additional, Karns, R., additional, Katzman, P.J., additional, Kawai, T., additional, Kelley, T.W., additional, Kent, J.W., additional, Kerr, E.H., additional, Kew, R.R., additional, Khalighi, M., additional, Khanh Vu, T.H., additional, Khong, T.Y., additional, Kim, B.S., additional, Kim, J., additional, Klein, M.J., additional, Knechtle, S.J., additional, Konkle, B.A., additional, Kowalewska, J., additional, Kricka, L.J., additional, Krishnan, B., additional, Kumar, A., additional, Kumar, S., additional, Kvietys, P., additional, Kwong, R.Y., additional, Lafont, E., additional, Laga, A.C., additional, Lagarrigue, S., additional, Lakin, A., additional, Laszik, Z.G., additional, Lauwers, G.Y., additional, Laver, N.V., additional, Lawlor, M.W., additional, Lederer, J.A., additional, Lee, R.E., additional, Lee, W.M., additional, LeGallo, R., additional, Leich, E., additional, Lemmens, B., additional, Le Pimpec-Barthes, F., additional, Leval, L., additional, Levy, B.D., additional, Lewis, J.S., additional, Lewis, T.L., additional, Leyva-Illades, D., additional, Li, L., additional, Li, Y.-P., additional, Lianidou, E.S., additional, Liao, L., additional, Liapis, H., additional, Lin, J.B., additional, Lin, A.-L., additional, Lindsay, M.E., additional, Liu, E., additional, Longacre, T., additional, Lopez-Alvarenga, J.C., additional, Lopez-Mejía, I., additional, Lozanski, G., additional, Lucia, M.S., additional, Luk, E., additional, Lutty, G.A., additional, Maclellan, R.A., additional, Madabhushi, A., additional, Mahindra, A., additional, Malek, E., additional, Mammucari, C., additional, Mani, H., additional, Mao, S.A., additional, Marboe, C.C., additional, Marí, M., additional, Marini, F., additional, Markou, A., additional, Marshall, A.H., additional, Martin, S.J., additional, Marzioni, M., additional, Masli, S., additional, Matsukuma, K.E., additional, Matulonis, U.A., additional, Mayfield, J., additional, McCoy, J.P., additional, McDougle, C.J., additional, McGinnis, M.R., additional, McGuire, A., additional, McKinstry, K.K., additional, McManus, B.M., additional, Means, A.L., additional, Meny, G.M., additional, Merchant, N., additional, Meserve, E.E.K, additional, Mess, A.M., additional, Minervini, M.I., additional, Mitchell, R.N., additional, Monaco, S.E., additional, Monga, S.P., additional, Monica Way, H.-Y., additional, Montecucco, C., additional, Montone, K.T., additional, Morgan, E.A., additional, Morgan, T.K., additional, Morrissey, K., additional, Mortensen, R.M., additional, Moser, S.A., additional, Mosquera, J.M., additional, Mossman, B.T., additional, Motta, A.C.F., additional, Mullins, E., additional, Murphy, G.F., additional, Murray, L., additional, Mysorekar, I.U., additional, Nadel, B., additional, Nadon, A.S., additional, Nagathihalli, N., additional, Nájera-Medina, O., additional, Nalesnik, M.A., additional, Nast, C.C., additional, Natkunam, Y., additional, Nault, J.C., additional, Nava-González, E.J., additional, Nayar, R., additional, Nerenz, R.D., additional, Neumann, H., additional, Ni, H., additional, Nolte, K.B., additional, Norton, L., additional, Nowak, J., additional, Nucera, C., additional, Nyberg, S.L., additional, Oakes, S.A., additional, Offerhaus, G.J.A., additional, Ojha, S., additional, Okabe, H., additional, Oliveira, A.M., additional, Osborn, E.A., additional, O'Tierney-Ginn, P., additional, Ott, G., additional, Ozcan, A., additional, Padera, R.F., additional, Pagano, M.B., additional, Page, E.K., additional, Paintal, A.S., additional, Pairon, J.-C., additional, Papadimitriou, J.C., additional, Park, H.-J., additional, Park, J.Y., additional, Parsons, L.N., additional, Patra, D., additional, Peclovits, A., additional, Peeters, P.M., additional, Perkins, T.N., additional, Perry, G., additional, Perumbeti, A., additional, Petersen, C.A., additional, Petrache, I., additional, Petroff, M.G., additional, Pettus, J.R., additional, Picken, M.M., additional, Pierson, C.R., additional, Pittman, M.E., additional, Pogoriler, J., additional, Politi, K., additional, Pollack, S.M., additional, Quintanilla-Martínez, L., additional, Rai, M.F., additional, Ramkissoon, S., additional, Randhawa, P.S., additional, Rangel, J.R., additional, Rasola, A., additional, Reeves, B., additional, Reheman, A., additional, Remick, D.G., additional, Reynaert, N.L., additional, Richmond, J.M., additional, Rivella, S., additional, Rivenbark, A.G., additional, Rizzuto, R., additional, Roberts, K.A., additional, Robin, D.A., additional, Robinson, L.J., additional, Rockey, D.C., additional, Rosenwald, A., additional, Rossetto, O., additional, Roth, K.A., additional, Roy-Chowdhury, J., additional, Roy-Chowdhury, N., additional, Rubin, M.A., additional, Rudnicki, M.A., additional, Russell, D.S., additional, Ryter, S.W., additional, Saban, D.R., additional, Sacher, R.A., additional, Sacks, D.B., additional, Sagaert, X., additional, Sagdeo, A., additional, Sahay, B., additional, Sahin, A., additional, Samali, A., additional, Sampson, B., additional, Sánchez-Escribano, R., additional, Sandri, M., additional, Sanyal, A., additional, Sasatomi, E., additional, Sauer, V., additional, Scherpereel, A., additional, Schmidt, E.P., additional, Schwabe, R.F., additional, Scorrano, L., additional, Scott, M.G., additional, Scull, J.C., additional, Seidman, M.A., additional, Seki, A., additional, Sellati, T.J., additional, Serban, K., additional, Serhan, C.N., additional, Seshan, S.V., additional, Seth, A., additional, Seykora, J.T., additional, Sharma, N., additional, Shi, C., additional, Shi, S.-R., additional, Shimada, M., additional, Shimizu, A., additional, Singer, D.B., additional, Sitko, K., additional, Smallwood, R.F., additional, Smiraglia, D.J., additional, Smith, B.R., additional, Smola, H., additional, Soubeyrand, M., additional, Stahl, W.L., additional, Stajić, M., additional, Stanworth, S.J., additional, Stathatos, N., additional, Stemler, K.M., additional, Stevens, T.M., additional, Stine, Z.E., additional, Stoll, M.L., additional, Strati, A., additional, Strutt, T.M., additional, Sund, M., additional, Sung, M.M., additional, Symonds, M.E., additional, Tabar, S., additional, Takahashi, N., additional, Talmadge, J.E., additional, Tang, V., additional, Tangrea, M., additional, Tarango, C., additional, Tario, J.D., additional, Taylor, C.R., additional, Taylor, R., additional, Tearney, G.J., additional, Tefera, K., additional, Thomas, S., additional, Thornburg, K.L., additional, Tirado, C.A., additional, Tobian, A.A.R., additional, Tomaszewski, J.E., additional, Tormey, C.A., additional, Torres, R., additional, Tran, M.-H., additional, Tredget, E.E., additional, Treister, N.S., additional, Trotter, J., additional, Troyer, D., additional, Truong, L., additional, Tubbs, R.R., additional, Turakhia, S., additional, Unglert, C.I., additional, Utheim, T., additional, Vahabzadeh, A., additional, van Bokhoven, A., additional, Vanden Berghe, T., additional, Vandenabeele, P., additional, van der Klei, I.J., additional, Vanguri, V.K., additional, Van Noorden, C.J.F, additional, Van Poznak, C., additional, Vassallo, R.R., additional, Vawda, R., additional, Vieth, M., additional, Visscher, D.W., additional, Volk, S.W., additional, Vyas, G.N., additional, Waggoner, S.N., additional, Walczak, H., additional, Walker, D.H., additional, Wallace, P.K., additional, Wanat, K.A., additional, Wang, J., additional, Wang, Y., additional, Wang, Y.X., additional, Warger, W.C., additional, Wei, S., additional, Weinman, S.A., additional, Wenig, B.M., additional, Wentz, S.C., additional, Werner, S., additional, Wertheim, G., additional, Whitley, E.M., additional, Wooderchak-Donahue, W., additional, Woods, K., additional, Wouters, E.F.M., additional, Wu, Y., additional, Xing, W., additional, Yachimski, P., additional, Yan, P., additional, Yang, J., additional, Yang, L., additional, Yoshizawa, S., additional, Yuan, J., additional, Yun, S.-H., additional, Yvon, A., additional, Zhang, H., additional, Zhang, P., additional, Zhao, Z., additional, Zhu, G., additional, Zhu, R., additional, Zordoky, B.N., additional, Zou, J., additional, Zuccato, J.A., additional, and Zucman-Rossi, J., additional

Published
2014
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42. Loss-of-function in RBBP5results in a syndromic neurodevelopmental disorder associated with microcephaly

Author

Huang, Yue, Jay, Kristy L., Yen-Wen Huang, Alden, Wan, Jijun, Jangam, Sharayu V., Chorin, Odelia, Rothschild, Annick, Barel, Ortal, Mariani, Milena, Iascone, Maria, Xue, Han, Acosta, Maria T., Adams, David R., Raquel, Alvarez, L., Alvey, Justin, Allworth, Aimee, Andrews, Ashley, Ashley, Euan A., Bacino, Carlos A., Bademci, Guney, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bellen, Hugo J., Bennett, Jimmy, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonner, Devon, Botto, Lorenzo, Briere, Lauren C., Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Carvhalo Neto, George D., Cassini, Thomas, Peter Chang, Ta Chen, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Chinn, Ivan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cope, Heidi, Corona, Rosario, Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D’Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G., Dell'Angelica, Esteban C., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L., Douine, Emilie D., Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Falk, Marni, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Gahl, William A., Glass, Ian, Gochuico, Bernadette, Goddard, Page C., Godfrey, Rena A., Grajewski, Alana, Hadley, Don, Halley, Meghan C., Hamid, Rizwan, Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Hutchison, Sarah, Introne, Wendy, Isasi, Rosario, Izumi, Kosuke, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Jean-Marie, Orpa, Jobanputra, Vaidehi, Kaitryn, Emerald, Ketkar, Shamika, Kiley, Dana, Kilich, Gonench, Kobren, Shilpa N., Kohane, Isaac S., Kohler, Jennefer N., Korrick, Susan, Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Lalani, Seema R., Lam, Byron, Lam, Christina, Lanpher, Brendan C., Lanza, Ian R., LeBlanc, Kimberly, Lee, Brendan H., Levitt, Roy, Lewis, Richard A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Maghiro, Audrey Stephannie, Mahoney, Rachel, Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McConkie-Rosell, Allyn, McCray, Alexa T., McGee, Elisabeth, Might, Matthew, Miller, Danny, Mirzaa, Ghayda, Moore, Ryan M., Morava, Eva, Moretti, Paolo, Mulvihill, John J., Nakano-Okuno, Mariko, Nelson, Stanley F., Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Palmer, Christina G.S., Papp, Jeanette C., Parker, Neil H., Phillips, John A., Posey, Jennifer E., Potocki, Lorraine, Pusey Swerdzewski, Barbara N., Quinlan, Aaron, Rao, Deepak A., Raper, Anna, Raskind, Wendy, Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenthal, Elizabeth, Rossignol, Francis, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, Daryl A., Seto, Elaine, Shashi, Vandana, Shelkowitz, Emily, Sheppeard, Sam, Shin, Jimann, Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solnica-Krezel, Lilianna, Solomon, Ben, Spillmann, Rebecca C., Stergachis, Andrew, Stoler, Joan M., Sullivan, Kathleen, Sullivan, Jennifer A., Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Queenie K.-G., Tan, Amelia L.M., Tarakad, Arjun, Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Ungar, Rachel A., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Walker, Melissa, Walley, Nicole M., Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Hubshman, Monika Weisz, Wener, Mark, Wenger, Tara, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Worley, Kim, Xiao, Changrui, Yamamoto, Shinya, Yang, John, Zhang, Zhe, Zuchner, Stephan, Huang, Jing, Mignot, Cyril, Keren, Boris, Saillour, Virginie, Mah-Som, Annelise Y., Sacharow, Stephanie, Rajabi, Farrah, Costin, Carrie, Yamamoto, Shinya, Kanca, Oguz, Bellen, Hugo J., Rosenfeld, Jill A., Palmer, Christina G.S., Nelson, Stanley F., Wangler, Michael F., and Martinez-Agosto, Julian A.

Abstract

Epigenetic dysregulation has been associated with many inherited disorders. RBBP5(HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease.

Published
2024
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43. The Undiagnosed Diseases Network: Characteristics of solvable applicants and diagnostic suggestions for nonaccepted ones

Author

Mulvihill, John J., Findley, Laura, Ni, Weihong, Sinsheimer, Janet S., Cole, F. Session, Esteves, Cecilia, Bernstein, Jonathan A., Newman, John H., Wheeler, Matthew T., Mokry, Jill R., Acosta, Maria T., Adams, David R., Afzali, Ben, Al-Beshri, Ali, Allworth, Aimee, Alvarez, Raquel L., Alvey, Justin, Andrews, Ashley, Ashley, Euan A., Bacino, Carlos A., Bademci, Guney, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bellen, Hugo J., Bennett, Jimmy, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonner, Devon, Borja, Nicholas, Botto, Lorenzo, Briere, Lauren C., Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Callaway, Kaitlin, Carey, John, Carvalho, George, Cassini, Thomas, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Chinn, Ivan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Corner, Brian, Corona, Rosario I., Craigen, William J., Crouse, Andrew B., Cuddapah, Vishnu, Cunningham, Michael, D’Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Delgado, Margaret, Dell’Angelica, Esteban C., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Douglas, Jessica, Douine, Emilie D., Earl, Dawn, Emrick, Lisa T., Eng, Christine M., Ezell, Kimberly, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Fu, Jiayu, Gahl, William A., Ganetzky, Rebecca, Glanton, Emily, Glass, Ian, Goddard, Page C., Gonzalez, Joanna M., Gropman, Andrea, Halley, Meghan C., Hamid, Rizwan, Hanchard, Neal, Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yan, Hurst, Anna, Introne, Wendy, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Marie, Orpa Jean-, Jobanputra, Vaidehi, Kaitryn, Emerald, Kanca, Oguz, Karasozen, Yigit, Ketkar, Shamika, Kiley, Dana, Kilich, Gonench, Kobren, Shilpa N., Kohane, Isaac S., Kohler, Jennefer N., Korf, Bruce, Korrick, Susan, Krakow, Deborah, Kravets, Elijah, Lalani, Seema R., Lam, Christina, Lanpher, Brendan C., Lanza, Ian R., Latchman, Kumarie, LeBlanc, Kimberly, Lee, Brendan H., Lewis, Richard A., Liu, Pengfei, Longo, Nicola, Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Maghiro, Audrey Stephannie, Mahoney, Rachel, Malicdan, May Christine V., Mao, Rong, Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McConkie-Rosell, Allyn, McCray, Alexa T., Might, Matthew, Mikati, Mohamad, Miller, Danny, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo, Morimoto, Marie, Mulvihill, John J., Nakano-Okuno, Mariko, Nelson, Stanley F., Neumann, Serena, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Parker, Neil H., Peart, LéShon, Petcharet, Leoyklang, Phillips, John A., Posey, Jennifer E., Potocki, Lorraine, Pusey Swerdzewski, Barbara N., Quinlan, Aaron, Rajagopalan, Ramakrishnan, Rao, Deepak A., Raper, Anna, Raskind, Wendy, Rebelo, Adriana, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rodriguez, Martin, Rosenfeld, Jill A., Rosenthal, Elizabeth, Rossignol, Francis, Ruzhnikov, Maura, Sabaii, Marla, Sampson, Jacinda B., Schedl, Timothy, Schoch, Kelly, Scott, Daryl A., Seto, Elaine, Shashi, Vandana, Shelkowitz, Emily, Sheppeard, Sam, Shin, Jimann, Silverman, Edwin K., Sisco, Kathy, Skelton, Tammi, Skraban, Cara, Smith, Carson A., Smith, Kevin S., Solnica-Krezel, Lilianna, Solomon, Ben, Spillmann, Rebecca C., Stergachis, Andrew, Stoler, Joan M., Sullivan, Kathleen, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Queenie K.-G., Tan, Amelia L.M., Tarakad, Arjun, Taylor, Herman, Tekin, Mustafa, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Ungar, Rachel A., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Walker, Melissa, Walley, Nicole M., Wambach, Jennifer, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Hubshman, Monika Weisz, Wener, Mark, Wenger, Tara, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Wood, Heidi, Worley, Kim, Yamamoto, Shinya, Zhang, Zhe, and Zuchner, Stephan

Abstract

Can certain characteristics identify as solvable some undiagnosed patients who seek extensive evaluation and thorough record review, such as by the Undiagnosed Diseases Network (UDN)?

Published
2024
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44. Dominant missense variants in SREBF2are associated with complex dermatological, neurological, and skeletal abnormalities

Author

Moulton, Matthew J., Atala, Kristhen, Zheng, Yiming, Dutta, Debdeep, Grange, Dorothy K., Lin, Wen-Wen, Wegner, Daniel J., Wambach, Jennifer A., Duker, Angela L., Bober, Michael B., Kratz, Lisa, Wise, Carol A., Oxendine, Ila, Khanshour, Anas, Bacino, Carlos A., Balasubramanyam, Ashok, Burrage, Lindsay C., Chao, Hsiao-Tuan, Chinn, Ivan, Clark, Gary D., Craigen, William J., Dai, Hongzheng, Emrick, Lisa T., Ketkar, Shamika, Lalani, Seema R., Lee, Brendan H., Lewis, Richard A., Marom, Ronit, Orengo, James P., Posey, Jennifer E., Potocki, Lorraine, Rosenfeld, Jill A., Seto, Elaine, Scott, Daryl A., Tarakad, Arjun, Tran, Alyssa A., Vogel, Tiphanie P., Hubshman, Monika Weisz, Worley, Kim, Bellen, Hugo J., Wangler, Michael F., Yamamoto, Shinya, Kanca, Oguz, Eng, Christine M., Liu, Pengfei, Ward, Patricia A., Behrens, Edward, Falk, Marni, Hassey, Kelly, Izumi, Kosuke, Kilich, Gonench, Sullivan, Kathleen, Vanderver, Adeline, Zhang, Zhe, Raper, Anna, Jobanputra, Vaidehi, Mikati, Mohamad, McConkie-Rosell, Allyn, Schoch, Kelly, Shashi, Vandana, Spillmann, Rebecca C., Tan, Queenie K.-G., Walley, Nicole M., Beggs, Alan H., Berry, Gerard T., Briere, Lauren C., Cobban, Laurel A., Coggins, Matthew, Fieg, Elizabeth L., High, Frances, Holm, Ingrid A., Korrick, Susan, Loscalzo, Joseph, Maas, Richard L., MacRae, Calum A., Pallais, J. Carl, Rao, Deepak A., Rodan, Lance H., Silverman, Edwin K., Stoler, Joan M., Sweetser, David A., Walker, Melissa, Douglas, Jessica, Glanton, Emily, Kobren, Shilpa N., Kohane, Isaac S., LeBlanc, Kimberly, Maghiro, Audrey Stephannie C., Mahoney, Rachel, McCray, Alexa T., Tan, Amelia L.M., Dasari, Surendra, Lanpher, Brendan C., Lanza, Ian R., Morava, Eva, Oglesbee, Devin, Bademci, Guney, Barbouth, Deborah, Bivona, Stephanie, Borja, Nicholas, Gonzalez, Joanna M., Latchman, Kumarie, Peart, LéShon, Rebelo, Adriana, Smith, Carson A., Tekin, Mustafa, Thorson, Willa, Zuchner, Stephan, Taylor, Herman, Colley, Heather A., Dayal, Jyoti G., Doss, Argenia L., Eckstein, David J., Hutchison, Sarah, Krasnewich, Donna M., Mamounas, Laura A., Manolio, Teri A., Urv, Tiina K., Acosta, Maria T., D'Souza, Precilla, Gropman, Andrea, Macnamara, Ellen F., Maduro, Valerie V., Mulvihill, John J., Novacic, Donna, Pusey Swerdzewski, Barbara N., Toro, Camilo, Wahl, Colleen E., Adams, David R., Afzali, Ben, Burke, Elizabeth A., Davis, Joie, Delgado, Margaret, Fu, Jiayu, Gahl, William A., Hanchard, Neil, Huang, Yan, Introne, Wendy, Jean-Marie, Orpa, Malicdan, May Christine V., Morimoto, Marie, Petcharet, Leoyklang, Rossignol, Francis, Sabaii, Marla, Solomon, Ben, Tifft, Cynthia J., Wolfe, Lynne A., Wood, Heidi, Allworth, Aimee, Bamshad, Michael, Beck, Anita, Bennett, Jimmy, Blue, Elizabeth, Byers, Peter, Chanprasert, Sirisak, Cunningham, Michael, Dipple, Katrina, Doherty, Daniel, Earl, Dawn, Glass, Ian, Hing, Anne, Hisama, Fuki M., Horike-Pyne, Martha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Kaitryn, Emerald, Lam, Christina, Miller, Danny, Mirzaa, Ghayda, Raskind, Wendy, Rosenthal, Elizabeth, Shelkowitz, Emily, Sheppeard, Sam, Stergachis, Andrew, Sybert, Virginia, Wener, Mark, Wenger, Tara, Alvarez, Raquel L., Bejerano, Gill, Bernstein, Jonathan A., Bonner, Devon, Coakley, Terra R., Fisher, Paul G., Goddard, Page C., Halley, Meghan C., Hom, Jason, Kohler, Jennefer N., Kravets, Elijah, Martin, Beth A., Marwaha, Shruti, Reuter, Chloe M., Ruzhnikov, Maura, Sampson, Jacinda B., Smith, Kevin S., Sutton, Shirley, Tabor, Holly K., Ungar, Rachel A., Wheeler, Matthew T., Ashley, Euan A., Byrd, William E., Crouse, Andrew B., Might, Matthew, Nakano-Okuno, Mariko, Whitlock, Jordan, Butte, Manish J., Corona, Rosario, Dell'Angelica, Esteban C., Dorrani, Naghmeh, Douine, Emilie D., Fogel, Brent L., Huang, Alden, Krakow, Deborah, Loo, Sandra K., Martin, Martin G., Martínez-Agosto, Julian A., McGee, Elisabeth, Nelson, Stanley F., Nieves-Rodriguez, Shirley, Papp, Jeanette C., Parker, Neil H., Renteria, Genecee, Sinsheimer, Janet S., Wan, Jijun, Alvey, Justin, Andrews, Ashley, Bale, Jim, Bohnsack, John, Botto, Lorenzo, Carey, John, Longo, Nicola, Moretti, Paolo, Pace, Laura, Quinlan, Aaron, Velinder, Matt, Viskochil, Dave, Marth, Gabor, Bayrak-Toydemir, Pinar, Mao, Rong, Westerfield, Monte, Bican, Anna, Cassini, Thomas, Corner, Brian, Hamid, Rizwan, Neumann, Serena, Phillips, John A., Rives, Lynette, Robertson, Amy K., Ezell, Kimberly, Cogan, Joy D., Hayes, Nichole, Kiley, Dana, Sisco, Kathy, Wambach, Jennifer, Wegner, Daniel, Baldridge, Dustin, Cole, F. Sessions, Pak, Stephen, Schedl, Timothy, Shin, Jimann, Solnica-Krezel, Lilianna, Wangler, Michael F., Yamamoto, Shinya, Cole, F. Sessions, Rios, Jonathan, and Bellen, Hugo J.

Abstract

We identified 2 individuals with de novo variants in SREBF2that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestations that partially overlap with sterol regulatory element binding proteins (SREBP) pathway-related disease phenotypes, but SREBF2-related disease has not been previously reported. Thus, we set out to assess the effects of SREBF2variants on SREBP pathway activation.

Published
2024
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45. Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder

Author

Kohler, Jennefer N., Legro, Nicole R., Baldridge, Dustin, Shin, Jimann, Bowman, Angela, Ugur, Berrak, Jackstadt, Madelyn M., Shriver, Leah P., Patti, Gary J., Zhang, Bo, Feng, Wenjia, McAdow, Anthony R., Goddard, Pagé, Ungar, Rachel A., Jensen, Tanner, Smith, Kevin S., Fresard, Laure, Alvarez, Raquel, Bonner, Devon, Reuter, Chloe M., McCormack, Colleen, Kravets, Elijah, Marwaha, Shruti, Holt, James M., Acosta, Maria T., Adam, Margaret, Adams, David R., Alvarez, Raquel L., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Bacino, Carlos A., Bademci, Guney, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bellen, Hugo J., Bennett, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Cassini, Thomas, Chang, Ta Chen Peter, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Chinn, Ivan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Sessions Cole, F., Colley, Heather A., Cope, Heidi, Corner, Brian, Corona, Rosario, Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D’Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G., Dell’Angelica, Esteban C., Dickson, Patricia, Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L., Douine, Emilie D., Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Ezell, Kimberly, Falk, Marni, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Gahl, William A., Glass, Ian, Gochuico, Bernadette, Goddard, Page C., Godfrey, Rena A., Golden-Grant, Katie, Grajewski, Alana, Hadley, Don, Hahn, Sihoun, Halley, Meghan C., Hamid, Rizwan, Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Hutchison, Sarah, Introne, Wendy, Isasi, Rosario, Izumi, Kosuke, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Jean-Marie, Orpa, Jobanputra, Vaidehi, Karaviti, Lefkothea, Ketkar, Shamika, Kiley, Dana, Kilich, Gonench, Kobren, Shilpa N., Kohane, Isaac S., Kohler, Jennefer N., Korrick, Susan, Kozuira, Mary, Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Lalani, Seema R., Lam, Byron, Lam, Christina, Lanpher, Brendan C., Lanza, Ian R., LeBlanc, Kimberly, Lee, Brendan H., Levitt, Roy, Lewis, Richard A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Maghiro, AudreyStephannie, Mahoney, Rachel, Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McConkie-Rosell, Allyn, McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Lawrence Merritt, J., Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo, Mulvihill, John, Nakano-Okuno, Mariko, Nelson, Stanley F., Neumann, Serena, Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Carl Pallais, J., Palmer, Christina G.S., Papp, Jeanette C., Parker, Neil H., Phillips, John A., Posey, Jennifer E., Potocki, Lorraine, Pusey Swerdzewski, Barbara N., Quinlan, Aaron, Rao, Deepak A., Raper, Anna, Raskind, Wendy, Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Rossignol, Francis, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, Daryl A., Ron Scott, C., Seto, Elaine, Shashi, Vandana, Shin, Jimann, Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solnica-Krezel, Lilianna, Solomon, Ben, Spillmann, Rebecca C., Stoler, Joan M., Sullivan, Kathleen, Sullivan, Jennifer A., Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Queenie K.-G., Tan, Amelia L.M., Tarakad, Arjun, Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Ungar, Rachel A., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Walker, Melissa, Wallace, Stephanie, Walley, Nicole M., Wambach, Jennifer, Wan, Jijun, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Hubshman, Monika Weisz, Wener, Mark, Wenger, Tara, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Worley, Kim, Xiao, Changrui, Yamamoto, Shinya, Yang, John, Zhang, Zhe, Zuchner, Stephan, Worthey, Elizabeth A., Ashley, Euan A., Montgomery, Stephen B., Fisher, Paul G., Postlethwait, John, De Camilli, Pietro, Solnica-Krezel, Lila, Bernstein, Jonathan A., and Wheeler, Matthew T.

Abstract

The function of FAM177A1and its relationship to human disease is largely unknown. Recent studies have demonstrated FAM177A1to be a critical immune-associated gene. One previous case study has linked FAM177A1to a neurodevelopmental disorder in 4 siblings.

Published
2024
Full Text
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46. Correction to ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder

Author

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

Subjects
Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC], Sciences du Vivant [q-bio]/Biotechnologies
Published
2020

47. De Novo ZMYND8variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations

Author

Dias, Kerith-Rae, Carlston, Colleen M., Blok, Laura E.R., De Hayr, Lachlan, Nawaz, Urwah, Evans, Carey-Anne, Bayrak-Toydemir, Pinar, Htun, Stephanie, Zhu, Ying, Ma, Alan, Lynch, Sally Ann, Moorwood, Catherine, Stals, Karen, Ellard, Sian, Bainbridge, Matthew N., Friedman, Jennifer, Pappas, John G., Rabin, Rachel, Nowak, Catherine B., Douglas, Jessica, Wilson, Theodore E., Guillen Sacoto, Maria J., Mullegama, Sureni V., Palculict, Timothy Blake, Kirk, Edwin P., Pinner, Jason R., Edwards, Matthew, Montanari, Francesca, Graziano, Claudio, Pippucci, Tommaso, Dingmann, Bri, Glass, Ian, Mefford, Heather C., Shimoji, Takeyoshi, Suzuki, Toshimitsu, Yamakawa, Kazuhiro, Streff, Haley, Schaaf, Christian P., Slavotinek, Anne M., Voineagu, Irina, Carey, John C., Buckley, Michael F., Schenck, Annette, Harvey, Robert J., and Roscioli, Tony

Abstract

ZMYND8encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8gene.

Published
2022
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