De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome

Elizabeth E Palmer; Seungbeom Hong; Fatema Al Zahrani; Mais O Hashem; Fajr A Aleisa; Heba M Jalal Ahmed; Tejaswi Kandula; Rebecca Macintosh; Andre E Minoche; Clare Puttick; Velimir Gayevskiy; Alexander P Drew; Mark J Cowley; Marcel Dinger; Jill A Rosenfeld; Rui Xiao; Megan T Cho; Suliat F Yakubu; Lindsay B Henderson; Maria J Guillen Sacoto; Amber Begtrup; Muddathir Hamad; Marwan Shinawi; Marisa V Andrews; Marilyn C Jones; Kristin Lindstrom; Ruth E Bristol; Saima Kayani; Molly Snyder; María Mercedes Villanueva; Angeles Schteinschnaider; Laurence Faivre; Christel Thauvin; Antonio Vitobello; Tony Roscioli; Edwin P Kirk; Ann Bye; Jasmeen Merzaban; Łukasz Jaremko; Mariusz Jaremko; Rani K Sachdev; Fowzan S Alkuraya; Stefan T Arold

doi:10.1016/j.ajhg.2019.01.013

De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome

Am J Hum Genet. 2019 Mar 7;104(3):542-552. doi: 10.1016/j.ajhg.2019.01.013. Epub 2019 Feb 28.

Authors

Elizabeth E Palmer¹, Seungbeom Hong², Fatema Al Zahrani³, Mais O Hashem³, Fajr A Aleisa², Heba M Jalal Ahmed², Tejaswi Kandula⁴, Rebecca Macintosh⁵, Andre E Minoche⁶, Clare Puttick⁶, Velimir Gayevskiy⁶, Alexander P Drew⁶, Mark J Cowley⁷, Marcel Dinger⁷, Jill A Rosenfeld⁸, Rui Xiao⁹, Megan T Cho¹⁰, Suliat F Yakubu², Lindsay B Henderson¹⁰, Maria J Guillen Sacoto¹⁰, Amber Begtrup¹⁰, Muddathir Hamad¹¹, Marwan Shinawi¹², Marisa V Andrews¹², Marilyn C Jones¹³, Kristin Lindstrom¹⁴, Ruth E Bristol¹⁵, Saima Kayani¹⁶, Molly Snyder¹⁷, María Mercedes Villanueva¹⁸, Angeles Schteinschnaider¹⁸, Laurence Faivre¹⁹, Christel Thauvin²⁰, Antonio Vitobello²⁰, Tony Roscioli²¹, Edwin P Kirk²², Ann Bye⁴, Jasmeen Merzaban²³, Łukasz Jaremko², Mariusz Jaremko²³, Rani K Sachdev⁴, Fowzan S Alkuraya²⁴, Stefan T Arold²⁵

Affiliations

¹ Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, University of New South Wales, Randwick, NSW 2031, Australia; The Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
² King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal 23955-6900, Saudi Arabia.
³ Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
⁴ Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, University of New South Wales, Randwick, NSW 2031, Australia.
⁵ Sydney Children's Hospital, Randwick, NSW 2031, Australia.
⁶ The Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
⁷ The Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW 2010, Australia.
⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA; Baylor Genetics, Houston, Texas 77021, USA.
¹⁰ GeneDx, Gaithersburg, Maryland 20877, USA.
¹¹ King Khalid University Hospital, King Saud University, Riyadh 11472, Saudi Arabia.
¹² Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
¹³ Division of Genetics, Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, California 92123, USA.
¹⁴ Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, Arizona 85016, USA.
¹⁵ Division of Pediatric Neurosurgery, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
¹⁶ University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
¹⁷ Department of Neurology, Children's Health, Dallas, Texas 75235, USA.
¹⁸ Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Montañeses, Buenos Aires 2325, Argentina.
¹⁹ Inserm U1231, Lipides, Nutrition, Cancer UMR 1231 Génétique des Anomalies du Développement, Burgundy University, Dijon 21079, France; Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, Dijon 21079, France.
²⁰ Inserm U1231, Lipides, Nutrition, Cancer UMR 1231 Génétique des Anomalies du Développement, Burgundy University, Dijon 21079, France.
²¹ Sydney Children's Hospital, Randwick, NSW 2031, Australia; New South Wales Health Pathology Genomic Laboratory, Prince of Wales Hospital, Randwick 2031, Australia; Neuroscience Research Australia, University of New South Wales 2031, Australia.
²² Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, University of New South Wales, Randwick, NSW 2031, Australia; New South Wales Health Pathology Genomic Laboratory, Prince of Wales Hospital, Randwick 2031, Australia.
²³ King Abdullah University of Science and Technology, Division of Biological and Environmental Sciences and Engineering, Thuwal 23955-6900, Saudi Arabia.
²⁴ Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.
²⁵ King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal 23955-6900, Saudi Arabia. Electronic address: stefan.arold@kaust.edu.sa.

Abstract

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.

Keywords: HX repeat; allelic disorders; developmental delay; dysmorphic; intellectual disability.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Motifs / genetics*
Child
Child, Preschool
Female
Genetic Variation*
Humans
Infant
Male
Nerve Tissue Proteins / genetics*
Neurocognitive Disorders / classification
Neurocognitive Disorders / etiology*
Neurocognitive Disorders / pathology
Phenotype
Prognosis
Repetitive Sequences, Nucleic Acid*
Syndrome

Substances

Nerve Tissue Proteins
atrophin-1