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1. Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine

Author

Víctor Faundes, Martin D. Jennings, Siobhan Crilly, Sarah Legraie, Sarah E. Withers, Sara Cuvertino, Sally J. Davies, Andrew G. L. Douglas, Andrew E. Fry, Victoria Harrison, Jeanne Amiel, Daphné Lehalle, William G. Newman, Patricia Newkirk, Judith Ranells, Miranda Splitt, Laura A. Cross, Carol J. Saunders, Bonnie R. Sullivan, Jorge L. Granadillo, Christopher T. Gordon, Paul R. Kasher, Graham D. Pavitt, and Siddharth Banka

Subjects
Science
Abstract

eIF5A is critical for protein synthesis but has not yet been associated with congenital human disease. Here, the authors show that EIF5A variants cause a Mendelian disorder via reduced eIF5A-ribosome interactions and this phenotype is partially corrected by spermidine supplementation in yeast and zebrafish.

Published
2021
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2. Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes

Author

Ana S.A. Cohen, Emily G. Farrow, Ahmed T. Abdelmoity, Joseph T. Alaimo, Shivarajan M. Amudhavalli, John T. Anderson, Lalit Bansal, Lauren Bartik, Primo Baybayan, Bradley Belden, Courtney D. Berrios, Rebecca L. Biswell, Pawel Buczkowicz, Orion Buske, Shreyasee Chakraborty, Warren A. Cheung, Keith A. Coffman, Ashley M. Cooper, Laura A. Cross, Tom Curran, Thuy Tien T. Dang, Mary M. Elfrink, Kendra L. Engleman, Erin D. Fecske, Cynthia Fieser, Keely Fitzgerald, Emily A. Fleming, Randi N. Gadea, Jennifer L. Gannon, Rose N. Gelineau-Morel, Margaret Gibson, Jeffrey Goldstein, Elin Grundberg, Kelsee Halpin, Brian S. Harvey, Bryce A. Heese, Wendy Hein, Suzanne M. Herd, Susan S. Hughes, Mohammed Ilyas, Jill Jacobson, Janda L. Jenkins, Shao Jiang, Jeffrey J. Johnston, Kathryn Keeler, Jonas Korlach, Jennifer Kussmann, Christine Lambert, Caitlin Lawson, Jean-Baptiste Le Pichon, James Steven Leeder, Vicki C. Little, Daniel A. Louiselle, Michael Lypka, Brittany D. McDonald, Neil Miller, Ann Modrcin, Annapoorna Nair, Shelby H. Neal, Christopher M. Oermann, Donna M. Pacicca, Kailash Pawar, Nyshele L. Posey, Nigel Price, Laura M.B. Puckett, Julio F. Quezada, Nikita Raje, William J. Rowell, Eric T. Rush, Venkatesh Sampath, Carol J. Saunders, Caitlin Schwager, Richard M. Schwend, Elizabeth Shaffer, Craig Smail, Sarah Soden, Meghan E. Strenk, Bonnie R. Sullivan, Brooke R. Sweeney, Jade B. Tam-Williams, Adam M. Walter, Holly Welsh, Aaron M. Wenger, Laurel K. Willig, Yun Yan, Scott T. Younger, Dihong Zhou, Tricia N. Zion, Isabelle Thiffault, and Tomi Pastinen

Subjects
Genome, Rare Diseases, High-Throughput Nucleotide Sequencing, Humans, Genomics, Sequence Analysis, DNA, Child, Genetics (clinical), Pedigree
Abstract

This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program.Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes.Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases).Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.

Published
2022

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

Author

Susan M. Hiatt, Slavica Trajkova, Matteo Rossi Sebastiano, E. Christopher Partridge, Fatima E. Abidi, Ashlyn Anderson, Muhammad Ansar, Stylianos E. Antonarakis, Azadeh Azadi, Ruxandra Bachmann-Gagescu, Andrea Bartuli, Caroline Benech, Jennifer L. Berkowitz, Michael J. Betti, Alfredo Brusco, Ashley Cannon, Giulia Caron, Yanmin Chen, Meagan E. Cochran, Tanner F. Coleman, Molly M. Crenshaw, Laurence Cuisset, Cynthia J. Curry, Hossein Darvish, Serwet Demirdas, Maria Descartes, Jessica Douglas, David A. Dyment, Houda Zghal Elloumi, Giuseppe Ermondi, Marie Faoucher, Emily G. Farrow, Stephanie A. Felker, Heather Fisher, Anna C.E. Hurst, Pascal Joset, Melissa A. Kelly, Stanislav Kmoch, Benjamin R. Leadem, Michael J. Lyons, Marina Macchiaiolo, Martin Magner, Giorgia Mandrile, Francesca Mattioli, Megan McEown, Sarah K. Meadows, Livija Medne, Naomi J.L. Meeks, Sarah Montgomery, Melanie P. Napier, Marvin Natowicz, Kimberly M. Newberry, Marcello Niceta, Lenka Noskova, Catherine B. Nowak, Amanda G. Noyes, Matthew Osmond, Eloise J. Prijoles, Jada Pugh, Verdiana Pullano, Chloé Quélin, Simin Rahimi-Aliabadi, Anita Rauch, Sylvia Redon, Alexandre Reymond, Caitlin R. Schwager, Elizabeth A. Sellars, Angela E. Scheuerle, Elena Shukarova-Angelovska, Cara Skraban, Elliot Stolerman, Bonnie R. Sullivan, Marco Tartaglia, Isabelle Thiffault, Kevin Uguen, Luis A. Umaña, Yolande van Bever, Saskia N. van der Crabben, Marjon A. van Slegtenhorst, Quinten Waisfisz, Camerun Washington, Lance H. Rodan, Richard M. Myers, Gregory M. Cooper, Human Genetics, Amsterdam Cardiovascular Sciences, Human genetics, CCA - Cancer biology and immunology, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], and Clinical Genetics

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, ZMYM3, transcriptional coregulators, MESH: Phenotype, MESH: Gene Expression Regulation, MESH: Nervous System Malformations, neurodevelopmental disorder, MESH: Male, MESH: Intellectual Disability, X-linked intellectual disability, chromatin modifiers, MESH: Histone Demethylases, Genetics, MESH: Female, MESH: Face, MESH: Nuclear Proteins, Genetics (clinical), MESH: Neurodevelopmental Disorders
Abstract

Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.

Published
2023

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

Author

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

Abstract

Neurodevelopmental disorders (NDDs) often result from highly penetrant variation in one of many genes, including genes not yet characterized. Using the MatchMaker Exchange, we assembled a cohort of 22 individuals with rare, protein-altering variation in the X-linked transcriptional coregulator gene ZMYM3. Most (n=19) individuals were males; 15 males had maternally-inherited alleles, three of the variants in males arose de novo, and one had unknown inheritance. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n=21) are missense, two of which are recurrent. Three unrelated males were identified with inherited variation at R441, a site at which variation has been previously reported in NDD-affected males, and two individuals have de novo variation at R1294. All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is highly expressed in the brain, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one mutant, ZMYM3R1274W, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to support a conclusive causative role for variation in ZMYM3 in disease, the totality of the evidence, including the presence of recurrent variation, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally-confirmed functional effects, strongly supports ZMYM3 as a novel NDD gene.

Published
2022

5. Insurance denials and diagnostic rates in a pediatric genomic research cohort

Author

Tricia N. Zion, Courtney D. Berrios, Ana S.A. Cohen, Lauren Bartik, Laura A. Cross, Kendra L. Engleman, Emily A. Fleming, Randi N. Gadea, Susan S. Hughes, Janda L. Jenkins, Jennifer Kussmann, Caitlin Lawson, Caitlin Schwager, Meghan E. Strenk, Holly Welsh, Eric T. Rush, Shivarajan M. Amudhavalli, Bonnie R. Sullivan, Dihong Zhou, Jennifer L. Gannon, Bryce A. Heese, Riley Moore, Emelia Boillat, Rebecca L. Biswell, Daniel A. Louiselle, Laura M.B. Puckett, Shanna Beyer, Shelby H. Neal, Victoria Sierant, Macy McBeth, Bradley Belden, Adam M. Walter, Margaret Gibson, Warren A. Cheung, Jeffrey J. Johnston, Isabelle Thiffault, Emily G. Farrow, Elin Grundberg, and Tomi Pastinen

Subjects
Genetics (clinical)
Published
2023

6. IGenomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes

Author

Jill Jacobson, Keith A Coffman, Susan S Hughes, Caitlin Lawson, Erin D Fecske, Ahmed T Abdelmoity, Thuy Tien T Dang, Annapoorna Nair, Janda L Jenkins, Kendra L Engleman, Daniel A Louiselle, Orion Buske, Nigel Price, Dihong Zhou, Michael Lypka, Courtney D Berrios, Laura Mb Puckett, Kelsee Halpin, Ana Sa Cohen, Nikita Raje, Aaron M Wenger, Emily G Farrow, Keely Fitzgerald, Mohammed Ilyas, Kailash Pawar, Joseph T Alaimo, Jennifer L Gannon, Laurel K Willig, Jean-Baptiste Le Pichon, Shivarajan M Amudhavalli, Christopher M Oermann, Rebecca L Biswell, Shelby H Neal, Lalit Bansal, Elizabeth Shaffer, Brittany D McDonald, Bonnie R Sullivan, Isabelle Thiffault, Christine Lambert, Ashley M Cooper, Suzanne M Herd, Holly Welsh, Julio F Quezada, Carol J Saunders, Caitlin Schwager, Brian S Harvey, Adam M Walter, Donna M Pacicca, Jennifer Kussmann, Rose N Gelineau-Morel, Margaret Gibson, Elin Grundberg, Shao Jiang, Scott T Younger, Steve Leeder, Richard M Schwend, John T Anderson, Venkatesh Sampath, Jonas Korlach, Bryce A Heese, Meghan E Strenk, Neil Miller, Vicki C Little, Ann Modrcin, Brooke R Sweeney, Randi N Gadea, Nyshele L Posey, Emily A Fleming, Wendy Hein, Cynthia Fieser, Eric T Rush, Laura A Cross, Craig Smail, William J Rowell, Kathryn Keeler, Jeffrey Goldstein, Tricia N Zion, Warren A. Cheung, Sarah Soden, Lauren Bartik, Bradley Belden, Thomas Curran, Pawel Buczkowicz, Shreyasee Chakraborty, Yun Yan, Tomi Pastinen, Primo Baybayan, Mary M Elfrink, Jeffrey J Johnston, and Jade B Tam-Williams

Subjects
Unknown Significance, Pedigree chart, Computational biology, Allele, Biology, Gene, Genome, Exome, DNA sequencing, Rare disease
Abstract

PURPOSETo provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids (GA4K) program.METHODSExtensive analyses of 960 families with suspected genetic disorders including short-read exome (ES) and genome sequencing (srGS); PacBio HiFi long-read GS (HiFi-GS); variant calling for small-nucleotide (SNV), structural (SV) and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants and pedigrees are stored in PhenoTips database, with data sharing through controlled access (dbGAP).RESULTSDiagnostic rates ranged from 11% for cases with prior negative genetic tests to 34.5% in naïve patients. Incorporating SVs from GS added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs than srGS. Variants and genes of unknown significance (VUS/GUS) remain the most common finding (58% of non-diagnostic cases).CONCLUSIONComputational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated by HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation, and by providing HiFi variant (SNV/SV) resources from >1,000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.

Published
2021

7. Correction: Corrigendum: Motivational, proteostatic and transcriptional deficits precede synapse loss, gliosis and neurodegeneration in the B6.HttQ111/+ model of Huntington’s disease

Author

Robert M. Bragg, Sydney R. Coffey, Rory M. Weston, Seth A. Ament, Jeffrey P. Cantle, Shawn Minnig, Cory C. Funk, Dominic D. Shuttleworth, Emily L. Woods, Bonnie R. Sullivan, Lindsey Jones, Anne Glickenhaus, John S. Anderson, Michael D. Anderson, Stephen B. Dunnett, Vanessa C. Wheeler, Marcy E. MacDonald, Simon P. Brooks, Nathan D. Price, and Jeffrey B. Carroll

Subjects
Multidisciplinary
Abstract

Scientific Reports 7: Article number: 41570; published online: 08 February 2017; updated: 28 March 2017 This Article contains a typographical error in the Methods section, under the subheading “Library construction, RNA Sequencing and RNASeq analysis”, where: “The fastq files were aligned using the default parameters of SNAPR50 (https://github.

Published
2017

8. Motivational, proteostatic and transcriptional deficits precede synapse loss, gliosis and neurodegeneration in the B6.Htt

Author

Lindsey Jones, Sydney R. Coffey, Vanessa C. Wheeler, Marcy E. MacDonald, Anne Glickenhaus, Stephen B. Dunnett, Jeffrey P. Cantle, Seth A. Ament, Rory M. Weston, Emily L. Woods, Robert M. Bragg, Jeffrey B. Carroll, Dominic D. Shuttleworth, Nathan D. Price, Michael D. Anderson, Bonnie R. Sullivan, Simon Philip Brooks, John S. Anderson, Cory C. Funk, and Shawn Minnig

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Inflammation, Disease, Striatum, Biology, Neuroprotection, Article, Synapse, 03 medical and health sciences, 0302 clinical medicine, Huntington's disease, medicine, Multidisciplinary, business.industry, Neurodegeneration, medicine.disease, Corrigenda, 030104 developmental biology, nervous system, Gliosis, medicine.symptom, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

We investigated the appearance and progression of disease-relevant signs in the B6.HttQ111/+mouse, a genetically precise model of the mutation that causes Huntington’s disease (HD). We find that B6.HttQ111/+mice are healthy, show no overt signs of central or peripheral inflammation, and no gross motor impairment as late as 12 months of age. Behaviorally, we find that 4-9 month old B6.HttQ111/+mice have normal activity levels and show no clear signs of anxiety or depression, but do show clear signs of reduced motivation. The neuronal density, neuronal size, synaptic density and number of glia is normal in B6.HttQ111/+striatum, the most vulnerable brain region in HD, up to 12 months of age. Despite this preservation of the synaptic and cellular composition of the striatum, we observe clear progressive, striatal-specific, transcriptional dysregulation and accumulation of neuronal intranuclear inclusions (NIIs). Simulation studies suggest these molecular endpoints are sufficiently robust for future preclinical studies, and that B6.HttQ111/+mice are a useful tool for modeling disease-modifying or neuroprotective strategies for disease processes before the onset of overt phenotypes.

Published
2016

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