Rare and de novo coding variants in chromodomain genes in Chiari I malformation

Brooke Sadler; Jackson Wilborn; Lilian Antunes; Timothy Kuensting; Andrew T Hale; Stephen R Gannon; Kevin McCall; Carlos Cruchaga; Matthew Harms; Norine Voisin; Alexandre Reymond; Gerarda Cappuccio; Nicola Brunetti-Pierri; Marco Tartaglia; Marcello Niceta; Chiara Leoni; Giuseppe Zampino; Allison Ashley-Koch; Aintzane Urbizu; Melanie E Garrett; Karen Soldano; Alfons Macaya; Donald Conrad; Jennifer Strahle; Matthew B Dobbs; Tychele N Turner; Chevis N Shannon; Douglas Brockmeyer; David D Limbrick; Christina A Gurnett; Gabe Haller

doi:10.1016/j.ajhg.2020.12.001

Rare and de novo coding variants in chromodomain genes in Chiari I malformation

Am J Hum Genet. 2021 Jan 7;108(1):100-114. doi: 10.1016/j.ajhg.2020.12.001. Epub 2020 Dec 21.

Authors

Brooke Sadler¹, Jackson Wilborn², Lilian Antunes³, Timothy Kuensting², Andrew T Hale⁴, Stephen R Gannon⁵, Kevin McCall³, Carlos Cruchaga⁶, Matthew Harms⁷, Norine Voisin⁸, Alexandre Reymond⁸, Gerarda Cappuccio⁹, Nicola Brunetti-Pierri⁹, Marco Tartaglia¹⁰, Marcello Niceta¹⁰, Chiara Leoni¹¹, Giuseppe Zampino¹¹, Allison Ashley-Koch¹², Aintzane Urbizu¹², Melanie E Garrett¹², Karen Soldano¹², Alfons Macaya¹³, Donald Conrad¹⁴, Jennifer Strahle², Matthew B Dobbs¹⁵, Tychele N Turner¹⁶, Chevis N Shannon⁴, Douglas Brockmeyer¹⁷, David D Limbrick², Christina A Gurnett¹⁸, Gabe Haller¹⁹

Affiliations

¹ Department of Pediatrics, Washington University, St. Louis, MO 63110, USA.
² Department of Neurosurgery, Washington University, St. Louis, MO 63110, USA.
³ Department of Orthopaedic Surgery, Washington University, St. Louis, MO 63110, USA.
⁴ Division of Genetic Medicine, Vanderbilt University Medical Center & Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
⁵ Division of Pediatric Neurosurgery and Surgical Outcomes Center for Kids, Monroe Carell Jr. Children's Hospital of Vanderbilt University, Nashville, TN 37232, USA.
⁶ Department of Psychiatry, Washington University, St. Louis, MO 63110, USA.
⁷ Department of Neurology, Columbia University, New York, NY 10027, USA.
⁸ Center for Integrative Genomics (CIG), University of Lausanne, Lausanne 1015, Switzerland.
⁹ Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples 80138, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli 80078, Italy.
¹⁰ Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00165, Italy.
¹¹ Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione-Policlinico-Universitario-A. Gemelli-IRCCS, Rome 00168, Italy.
¹² Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC 27708, USA.
¹³ Pediatric Neurology Research group, University Hospital Vall d'Hebron, Barcelona 08035, Spain.
¹⁴ Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA.
¹⁵ Department of Orthopaedic Surgery, Washington University, St. Louis, MO 63110, USA; Shriners Hospital for Children, St. Louis, MO 63110, USA.
¹⁶ Department of Genetics, Washington University, St. Louis, MO 63110, USA.
¹⁷ Department of Neurological Surgery, University of Utah, Primary Children's Hospital, Salt Lake City, UT 84113, USA.
¹⁸ Department of Pediatrics, Washington University, St. Louis, MO 63110, USA; Department of Orthopaedic Surgery, Washington University, St. Louis, MO 63110, USA; Department of Neurology, Washington University, St. Louis, MO 63110, USA.
¹⁹ Department of Neurosurgery, Washington University, St. Louis, MO 63110, USA; Department of Neurology, Washington University, St. Louis, MO 63110, USA; Department of Genetics, Washington University, St. Louis, MO 63110, USA. Electronic address: ghaller@wustl.edu.

Abstract

Chiari I malformation (CM1), the displacement of the cerebellum through the foramen magnum into the spinal canal, is one of the most common pediatric neurological conditions. Individuals with CM1 can present with neurological symptoms, including severe headaches and sensory or motor deficits, often as a consequence of brainstem compression or syringomyelia (SM). We conducted whole-exome sequencing (WES) on 668 CM1 probands and 232 family members and performed gene-burden and de novo enrichment analyses. A significant enrichment of rare and de novo non-synonymous variants in chromodomain (CHD) genes was observed among individuals with CM1 (combined p = 2.4 × 10^-10), including 3 de novo loss-of-function variants in CHD8 (LOF enrichment p = 1.9 × 10^-10) and a significant burden of rare transmitted variants in CHD3 (p = 1.8 × 10^-6). Overall, individuals with CM1 were found to have significantly increased head circumference (p = 2.6 × 10^-9), with many harboring CHD rare variants having macrocephaly. Finally, haploinsufficiency for chd8 in zebrafish led to macrocephaly and posterior hindbrain displacement reminiscent of CM1. These results implicate chromodomain genes and excessive brain growth in CM1 pathogenesis.

Keywords: Chiari I malformation; chromodomain genes; de novo mutations; gene burden; macrocephaly; rare variants; zebrafish disease model.

MeSH terms

Adult
Animals
Arnold-Chiari Malformation / genetics*
Arnold-Chiari Malformation / pathology
Brain / pathology
Case-Control Studies
DNA-Binding Proteins / genetics*
Exome Sequencing / methods
Female
Haploinsufficiency / genetics
Humans
Magnetic Resonance Imaging / methods
Male
Polymorphism, Single Nucleotide / genetics*
Syringomyelia / genetics
Zebrafish / genetics

Substances

DNA-Binding Proteins

Abstract

MeSH terms

Substances

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