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Language: English

In: The American Journal of Human Genetics, 05 January 2017, Vol.100(1), pp.128-137

Description: Early B cell factor 3 ( ) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses expression. However, human neurodevelopmental disorders related to have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in . Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in cause a genetic neurodevelopmental syndrome and suggest that loss of function might mediate a subset of neurologic phenotypes shared by -related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.

Keywords: Drosophila ; Knot ; Ataxia ; Hypotonia ; Intellectual Disability ; Expressive Speech Disorder ; Coe3 ; Transcription Factor ; Vermian Hypoplasia ; Inhibitory Gabaergic Neurons ; Biology

ISSN: 0002-9297

E-ISSN: 1537-6605

DOI: 10.1016/j.ajhg.2016.11.018

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URL: View full text in ScienceDirect

Language: English

In: The American Journal of Human Genetics, 01 March 2018, Vol.102(3), pp.494-504

Description: ATP synthase, H transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in , who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C〉T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T〉G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F F ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of , the homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human In contrast, expression of the c.245C〉T and c.317T〉G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C〉T (p.Pro82Leu) and c.317T〉G (p.Val106Gly) in as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation.

Keywords: Mitochondrial Disease ; Complex V ; ATP Synthase ; Exome Sequencing ; Oxidative Phosphorylation ; Lactic Acidosis ; Hyperammonemia ; 3-Methylglutaric Aciduria ; Model Organism ; Fibroblast ; Biology

ISSN: 0002-9297

E-ISSN: 1537-6605

DOI: 10.1016/j.ajhg.2018.01.020

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Language: English

In: The American Journal of Human Genetics, 02 February 2017, Vol.100(2), pp.343-351

Description: Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C〉T (p.Arg298Trp) variant in the nucleus accumbens associated 1 ( ) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10 ). Selective constraint against missense variants in makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in .

Keywords: Nacc1 ; Cataracts ; Microcephaly ; Epilepsy ; Whole-Exome Sequencing ; Developmental/Intellectual Disabilities ; Stereotypy ; Irritability ; Biology

ISSN: 0002-9297

E-ISSN: 1537-6605

DOI: 10.1016/j.ajhg.2016.12.013

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Language: English

In: The American Journal of Human Genetics, 02 February 2017, Vol.100(2), pp.185-192

Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1016/j.ajhg.2017.01.006 Byline: Rachel B. Ramoni [rachelramoni@nyu.edu] (1,2,*), John J. Mulvihill (3), David R. Adams (3), Patrick Allard (4,5), Euan A. Ashley (6), Jonathan A. Bernstein (7), William A. Gahl (3), Rizwan Hamid (8), Joseph Loscalzo (9), Alexa T. McCray (1), Vandana Shashi (10), Cynthia J. Tifft (3), David R. Adams, Christopher J. Adams, Mercedes E. Alejandro, Patrick Allard, Euan A. Ashley, Mashid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Alan H. Beggs, Hugo J. Bellen, David Bernick, Jonathan A. Bernstein, Anna Bican, David P. Bick, Camille L. Birch, Braden E. Boone, Lauren C. Briere, Donna M. Brown, Catherine A. Brownstein, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Katherine R. Chao, Gary D. Clark, Joy D. Cogan, Cynthia M. Cooper, William J. Craigen, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Daniel C. Dorset, David D. Draper, Annika M. Dries, Rachel Eastwood, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Paul G. Fisher, Trevor S. Frisby, Kate Frost, William A. Gahl, Valerie Gartner, Rena A. Godfrey, Mitchell Goheen, Gretchen A. Golas, David B. Goldstein, Mary "Gracie" G. Gordon, Sarah E. Gould, Jean-Philippe F. Gourdine, Brett H. Graham, Catherine A. Groden, Andrea L. Gropman, Mary E. Hackbarth, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Lori H. Handley, Isabel Hardee, Matthew R. Herzog, Ingrid A. Holm, Ellen M. Howerton, Brenda Iglesias, Howard J. Jacob, Mahim Jain, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Alanna E. Koehler, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Lea Latham, Yvonne L. Latour, C. Christopher Lau, Jozef Lazar, Brendan H. Lee, Hane Lee, Paul R. Lee, Shawn E. Levy, Denise J. Levy, Richard A. Lewis, Adam P. Liebendorder, Sharyn A. Lincoln, Carson R. Loomis, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Casey Martin, Paul Mazur, Alexandra J. McCarty, Allyn McConkie-Rosell, Alexa T. McCray, Thomas O. Metz, Matthew Might, Paolo M. Moretti, John J. Mulvihill, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Loren D.M. Pena, John A. Phillips III, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Rachel B. Ramoni, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Sarah Sadozai, Katherine E. Schaffer, Kelly Schoch, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Vandana Shashi, Edwin K. Silverman, Janet S. Sinsheimer, Ariane G. Soldatos, Rebecca C. Spillmann, Kimberly Splinter, Joan M. Stoler, Nicholas Stong, Kimberly A. Strong, Jennifer A. Sullivan, David A. Sweetser, Sara P. Thomas, Cynthia J. Tifft, Nathanial J. Tolman, Camilo Toro, Alyssa A. Tran, Zaheer M. Valivullah, Eric Vilain, Daryl M. Waggott, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Michael F. Wangler, Mike Warburton, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Alec A. Weech, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Elizabeth A. Worthey, Shinya Yamamoto, Yaping Yang, Guoyun Yu, Patricia A. Zornio Keywords rare diseases; diagnosis; National Institutes of Health; cooperative behavior; phenotyping; high-throughput nucleotide sequencing Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science. Author Affiliation: (1) Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA (2) Department of Epidemiology and Health Promotion, New York University College of Dentistry, New York, NY 10010, USA (3) National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA (4) Institute for Society and Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA (5) Department of Environmental Health Sciences, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA 90095 USA (6) Departments of Medicine and Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA (7) Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA (8) Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA (9) Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA (10) Department of Pediatrics, Duke University School of Medicine, Durham, NC 27707, USA * Corresponding author

Keywords: Rare Diseases ; Diagnosis ; National Institutes of Health ; Cooperative Behavior ; Phenotyping ; High-Throughput Nucleotide Sequencing ; Biology

ISSN: 0002-9297

E-ISSN: 1537-6605

DOI: 10.1016/j.ajhg.2017.01.006

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Language: English

In: The American Journal of Human Genetics, 01 June 2017, Vol.100(6), pp.843-853

Description: One major challenge encountered with interpreting human genetic variants is the limited understanding of the functional impact of genetic alterations on biological processes. Furthermore, there remains an unmet demand for an efficient survey of the wealth of information on human homologs in model organisms across numerous databases. To efficiently assess the large volume of publically available information, it is important to provide a concise summary of the most relevant information in a rapid user-friendly format. To this end, we created MARRVEL (model organism aggregated resources for rare variant exploration). MARRVEL is a publicly available website that integrates information from six human genetic databases and seven model organism databases. For any given variant or gene, MARRVEL displays information from OMIM, ExAC, ClinVar, Geno2MP, DGV, and DECIPHER. Importantly, it curates model organism-specific databases to concurrently display a concise summary regarding the human gene homologs in budding and fission yeast, worm, fly, fish, mouse, and rat on a single webpage. Experiment-based information on tissue expression, protein subcellular localization, biological process, and molecular function for the human gene and homologs in the seven model organisms are arranged into a concise output. Hence, rather than visiting multiple separate databases for variant and gene analysis, users can obtain important information by searching once through MARRVEL. Altogether, MARRVEL dramatically improves efficiency and accessibility to data collection and facilitates analysis of human genes and variants by cross-disciplinary integration of 18 million records available in public databases to facilitate clinical diagnosis and basic research.

Keywords: Rare Diseases ; Genetic Diseases ; Variants of Unknown Significance ; Flybase ; Zfin ; Mgi ; Diopt ; Exac ; Clinvar ; Geno2mp ; Biology

ISSN: 0002-9297

E-ISSN: 1537-6605

DOI: 10.1016/j.ajhg.2017.04.010

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Language: English

In: The American Journal of Human Genetics, 02 August 2018, Vol.103(2), pp.245-260

Description: Interferon regulatory factor 2 binding protein-like ( ) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in and are affected with neurological symptoms Five individuals who carry nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly ortholog, called (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that and are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

Keywords: Hypotonia ; Developmental Regression ; Ataxia ; Seizures ; Drosophila ; Pits ; Cg11138 ; Neurodegeneration ; C3hc4 Ring Finger ; Eap1 ; Biology

ISSN: 0002-9297

E-ISSN: 1537-6605

DOI: 10.1016/j.ajhg.2018.07.006

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Language: English

In: The American Journal of Human Genetics, 06 September 2018, Vol.103(3), pp.456-456

Keywords: Biology

ISSN: 0002-9297

E-ISSN: 1537-6605

DOI: 10.1016/j.ajhg.2018.08.010

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In: The American Journal of Human Genetics, 06 October 2016, Vol.99(4), pp.991-999

Description: The genes ( , , and ) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in and have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the associated condition from - and -related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the genes.

Keywords: Asxl2 ; Macrocephaly ; Whole-Exome Sequencing ; Developmental Delay ; Intellectual Disability ; Glabellar Nevus Flammeus ; Biology

ISSN: 0002-9297

E-ISSN: 1537-6605

DOI: 10.1016/j.ajhg.2016.08.017

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In: Neurology: Genetics, 2018, Vol.4(4)

Keywords: 14 ; 91 ; 162 ; 191 ; Clinical/Scientific Notes;

ISSN: 2376-7839

DOI: 10.1212/NXG.0000000000000248

URL: View record at Wolters Kluwer Health Ovid Technologies

Language: English

In: The American Journal of Human Genetics, 07 March 2019, Vol.104(3), pp.422-438

Description: SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in , which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a zebrafish model both support the hypomorphic nature of the identified variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) ; this rescue is consistent with the hypothesis that hypomorphic variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

Keywords: Exome Sequencing ; Tonsl ; DNA Replication ; DNA Repair ; Sponastrime Dysplasia ; Skeletal Dysplasia ; Biology

ISSN: 0002-9297

E-ISSN: 1537-6605

DOI: 10.1016/j.ajhg.2019.01.007

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