Paralog Studies Augment Gene Discovery: DDX and DHX Genes

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

doi:10.1016/j.ajhg.2019.06.001

Paralog Studies Augment Gene Discovery: DDX and DHX Genes

Am J Hum Genet. 2019 Aug 1;105(2):302-316. doi: 10.1016/j.ajhg.2019.06.001. Epub 2019 Jun 27.

Authors

Ingrid Paine¹, Jennifer E Posey¹, Christopher M Grochowski¹, Shalini N Jhangiani², Sarah Rosenheck³, Robert Kleyner³, Taylor Marmorale³, Margaret Yoon³, Kai Wang⁴, Reid Robison⁵, Gerarda Cappuccio⁶, Michele Pinelli⁶, Adriano Magli⁷, Zeynep Coban Akdemir¹, Joannie Hui⁸, Wai Lan Yeung⁹, Bibiana K Y Wong¹⁰, Lucia Ortega¹¹, Mir Reza Bekheirnia¹², Tatjana Bierhals¹³, Maja Hempel¹³, Jessika Johannsen¹⁴, René Santer¹⁴, Dilek Aktas¹⁵, Mehmet Alikasifoglu¹⁵, Sevcan Bozdogan¹⁶, Hatip Aydin¹⁷, Ender Karaca¹⁸, Yavuz Bayram¹⁹, Hadas Ityel²⁰, Michael Dorschner²¹, Janson J White²², Ekkehard Wilichowski²³, Saskia B Wortmann²⁴, Erasmo B Casella²⁵, Joao Paulo Kitajima²⁶, Fernando Kok²⁷, Fabiola Monteiro²⁶, Donna M Muzny²⁸, Michael Bamshad²⁹, Richard A Gibbs²⁸, V Reid Sutton¹; University of Washington Center for Mendelian Genomics, Baylor-Hopkins Center for Mendelian Genomics, Telethon Undiagnosed Diseases Program; Hilde Van Esch³⁰, Nicola Brunetti-Pierri⁶, Friedhelm Hildebrandt²⁰, Ariel Brautbar¹¹, Ignatia B Van den Veyver³¹, Ian Glass³², Davor Lessel¹³, Gholson J Lyon³³, James R Lupski³⁴

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
² Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
³ Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, NY 11724, USA.
⁴ Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁵ Utah Foundation for Biomedical Research, Salt Lake City, UT 84107, USA.
⁶ Department of Translational Medicine, University of Naples "Federico II," 80131 Napoli, Italy; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy.
⁷ Department of Pediatric Ophthalmology, University of Salerno, 84081 Baronissi SA, Italy.
⁸ Department of Pediatrics, Prince of Wales Hospital, the Chinese University of Hong Kong, Hong Kong SAR, China.
⁹ Department of Pediatrics and Adolescent Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong SAR, China.
¹⁰ Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA; The Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
¹¹ Medical Genetics Department, Cook Children's Hospital, Fort Worth, TX 76104, USA.
¹² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Section of Pediatric Renal, Baylor College of Medicine, Houston, TX 77030, USA; Department of Genetics, Texas Children's Hospital, Houston, TX 76104, USA.
¹³ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
¹⁴ Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
¹⁵ DAMAGEN Genetic Diagnostic Center, 06690 Ankara, Turkey.
¹⁶ Department of Medical Genetics, Cukurova University Faculty of Medicine, 01330 Adana, Turkey.
¹⁷ Department of Medical Genetics, Medical Faculty of Namik Kemal University, Tekirdag 59100, Turkey.
¹⁸ Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
¹⁹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA.
²⁰ Division of Nephrology, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
²¹ Center for Precision Diagnostics, University of Washington, Seattle, WA 98195, USA.
²² Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
²³ Department of Pediatrics and Pediatric Neurology, Georg-August-Universität Göttingen, 37075 Göttingen, Germany.
²⁴ Institute of Human Genetics, Technical University München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum Munchen, 85764 Neuherberg, Germany; University Children's Hospital, Paracelsus Medical University, 5020 Salsburg, Austria.
²⁵ Children's Institute, Hospital das Clinicas, University of Sao Paulo, 05405-000 Sao Paulo, Brazil.
²⁶ Mendelics Genomic Analysis, 04013-000 Sao Paulo, Brazil.
²⁷ Mendelics Genomic Analysis, 04013-000 Sao Paulo, Brazil; Department of Neurology, University of Sao Paulo School of Medicine, 01246-903 Sao Paulo, Brazil.
²⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
²⁹ Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
³⁰ Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
³¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA; The Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
³² Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
³³ Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, NY 11724, USA; Utah Foundation for Biomedical Research, Salt Lake City, UT 84107, USA; Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
³⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: [email protected].

Abstract

Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.

Keywords: DExD/H-box RNA helicase family; developmental delay; human paralogs; intellectual disability.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

DEAD-box RNA Helicases / genetics*
Exome Sequencing
Female
Genetic Association Studies
Humans
Infant
Infant, Newborn
Male
Mutation, Missense*
Neoplasm Proteins / genetics*
Neurodevelopmental Disorders / genetics*
Neurodevelopmental Disorders / pathology*
Pedigree
RNA Helicases / genetics*

Substances

Neoplasm Proteins
DDX54 protein, human
DHX16 protein, human
DHX34 protein, human
DEAD-box RNA Helicases
RNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding