Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

CAUSES Study, SPARK Consortium

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype–phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. Methods: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. Results: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188–221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. Conclusions: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Original languageEnglish (US)
Article number63
JournalGenome medicine
Volume13
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
We thank all of the families participating in this study. We are grateful to all of the families at the participating SSC sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base for both SSC and SPARK samples, as well as SPARK exome data from the SPARK Consortium. Approved researchers can obtain the SSC population dataset described in this study ( https://www.sfari.org/resource/resources/simons-simplex-collection/ ) by applying at https://base.sfari.org . We thank the DDD study, which presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. The authors would like to thank the University of Washington Center for Mendelian Genomics and all contributors to MyGene2 for use of data included in MyGene2. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank Emily Guilbert for aid in recontacting a family included in this study. We thank Tonia Brown for assistance in editing this manuscript and Amy Wilfert for advice on statistics.

Funding Information:
This work was supported, in part, by the U.S. National Institutes of Health (R01MH101221) to E.E.E. Research reported in this publication was supported, in part, by the National Institute of Neurological Disorders and Stroke (NINDS) under award number K08NS092898, Jordan’s Guardian Angels, and the Brotman Baty Institute (to G.M.M.). M.I., A.C., and A.S. were supported by the G.E.N.E. (Genomic analysis Evaluation Network) Research Project founded by Progetti di Innovazione in Ambito Sanitario e Socio Sanitario (Bando EX decreto n.2713 28.02.2018) Regione Lombardia. D. L was supported by the German Research Foundation (DFG; LE 4223/1). B.B.A.d.V. and L.E.L.M.V. were supported by grants from the Dutch Organization for Health Research and Development (ZON-MW grants 917–86–319 and 912–12–109). M.E., O.G., and C.R. received funding from the Italian Ministry of Health (Project RC n. 2757328). I.T. is supported by generous donors to the Children’s Mercy Research Institute and the Genomic Answers for Kids program. K.X. is supported by the National Natural Science Foundation of China (NSFC: 8173000779) and the Science and Technology Major Project of Hunan Provincial Science and Technology Department (2018SK1030). M.A.G. was supported by the U.S. National Institutes of Health (T32HG000035). E.E.E. is an investigator of the Howard Hughes Medical Institute.

Funding Information:
We thank all of the families participating in this study. We are grateful to all of the families at the participating SSC sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base for both SSC and SPARK samples, as well as SPARK exome data from the SPARK Consortium. Approved researchers can obtain the SSC population dataset described in this study (https://www.sfari.org/resource/resources/simons-simplex-collection/) by applying at https://base.sfari.org. We thank the DDD study, which presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. The authors would like to thank the University of Washington Center for Mendelian Genomics and all contributors to MyGene2 for use of data included in MyGene2. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank Emily Guilbert for aid in recontacting a family included in this study. We thank Tonia Brown for assistance in editing this manuscript and Amy Wilfert for advice on statistics. Consortia SPARK Consortium: John Acampado1, Andrea J. Ace1, Alpha Amatya1, Irina Astrovskaya1, Asif Bashar1, Elizabeth Brooks1, Martin E. Butler1, Lindsey A. Cartner1, Wubin Chin1, Wendy K. Chung1,2, Amy M. Daniels1, Pamela Feliciano1, Chris Fleisch1, Swami Ganesan1, William Jensen1, Alex E. Lash1, Richard Marini1, Vincent J. Myers1, Eirene O?Connor1, Chris Rigby1, Beverly E. Robertson1, Neelay Shah1, Swapnil Shah1, Emily Singer1, LeeAnne G. Snyder1, Alexandra N. Stephens1, Jennifer Tjernagel1, Brianna M. Vernoia1, Natalia Volfovsky1, Loran Casey White1, Alexander Hsieh2, Yufeng Shen2, Xueya Zhou2, Tychele N. Turner3, Ethan Bahl4, Taylor R. Thomas4, Leo Brueggeman4, Tanner Koomar4, Jacob J. Michaelson4, Brian J. O?Roak5, Rebecca A. Barnard5, Richard A. Gibbs6, Donna Muzny6, Aniko Sabo6, Kelli L. Baalman Ahmed6, Evan E. Eichler7, Matthew Siegel8, Leonard Abbeduto9, David G. Amaral9, Brittani A. Hilscher9, Deana Li9, Kaitlin Smith9, Samantha Thompson9, Charles Albright10, Eric M. Butter10, Sara Eldred10, Nathan Hanna10, Mark Jones10, Daniel Lee Coury10, Jessica Scherr10, Taylor Pifher10, Erin Roby10, Brandy Dennis10, Lorrin Higgins10, Melissa Brown10, Michael Alessandri11, Anibal Gutierrez11, Melissa N. Hale11, Lynette M. Herbert11, Hoa Lam Schneider11, Giancarla David11, Robert D. Annett12, Dustin E. Sarver12, Ivette Arriaga13, Alexies Camba13, Amanda C. Gulsrud13, Monica Haley13, James T. McCracken13, Sophia Sandhu13, Maira Tafolla13, Wha S. Yang13, Laura A. Carpenter14, Catherine C. Bradley14, Frampton Gwynette14, Patricia Manning15, Rebecca Shaffer15, Carrie Thomas15, Raphael A. Bernier16, Emily A. Fox16, Jennifer A. Gerdts16, Micah Pepper16, Theodore Ho16, Daniel Cho16, Joseph Piven17, Holly Lechniak18, Latha V. Soorya18, Rachel Gordon18, Allison Wainer18, Lisa Yeh18, Cesar Ochoa-Lubinoff19, Nicole Russo19, Elizabeth Berry-Kravis20, Stephanie Booker21, Craig A. Erickson21, Lisa M. Prock22, Katherine G. Pawlowski22, Emily T. Matthews22, Stephanie J. Brewster22, Margaret A. Hojlo22, Evi Abada22, Elena Lamarche23, Tianyun Wang24, Shwetha C. Murali24, William T. Harvey24, Hannah E. Kaplan25, Karen L. Pierce25, Lindsey DeMarco26, Susannah Horner26, Juhi Pandey26, Samantha Plate?26, Mustafa Sahin27, Katherine D. Riley27, Erin Carmody27, Julia Constantini7, Amy Esler28, Ali Fatemi29, Hanna Hutter29, Rebecca J. Landa29, Alexander P. McKenzie29, Jason Neely29, Vini Singh29, Bonnie Van Metre29, Ericka L. Wodka29, Eric J. Fombonne30, Lark Y. Huang-Storms30, Lillian D. Pacheco30, Sarah A. Mastel30, Leigh A. Coppola30, Sunday Francis31, Andrea Jarrett31, Suma Jacob31, Natasha Lillie31, Jaclyn Gunderson31, Dalia Istephanous31, Laura Simon31, Ori Wasserberg31, Angela L. Rachubinski32, Cordelia R. Rosenberg32, Stephen M. Kanne33,34, Amanda D. Shocklee34, Nicole Takahashi34, Shelby L. Bridwell34, Rebecca L. Klimczac34, Melissa A. Mahurin34, Hannah E. Cotrell34, Cortaiga A. Grant34, Samantha G. Hunter34, Christa Lese Martin35, Cora M. Taylor35, Lauren K. Walsh35, Katherine A. Dent35, Andrew Mason36, Anthony Sziklay36, Christopher J. Smith36.1Simons Foundation, New York, USA2Columbia University, New York, USA3Washington University School of Medicine, St. Louis, USA4University of Iowa Carver College of Medicine, Iowa City, USA5Oregon Health & Science University, Portland, USA6Baylor College of Medicine, Houston, USA7University of Washington School of Medicine, Howard Hughes Medical Institute, Seattle, USA8Maine Medical Center Research Institute, Portland, USA9University of California, Davis, Sacramento, USA10Nationwide Children?s Hospital, Columbus, USA11University of Miami, Coral Gables, USA12University of Mississippi Medical Center, Jackson, USA13University of California, Los Angeles, Los Angeles, USA14Medical University of Southern Carolina (MUSC), Portland, USA15Cincinnati Children?s Hospital Medical Center ? Research Foundation, Cincinnati, USA16Seattle Children?s Autism Center/UW, Seattle, USA17University of North Carolina at Chapel Hill, Chapel Hill, USA18Department of Child & Adolescent Psychiatry, Rush University Medical Center, Chicago, USA19Department of Developmental & Behavioral Pediatrics, Rush University Medical Center, Chicago, USA20Department of Neurological Sciences, Department of Pediatrics, Department of Biochemistry, Rush University Medical Center, Chicago, USA21Cincinnati Children?s Hospital Medical Center ? Research Foundation, Cincinnati, USA22Boston Children?s Hospital (BCH), Boston, USA23University of North Carolina at Chapel Hill, Chapel Hill, USA24University of Washington School of Medicine, Seattle, USA25University of California, San Diego, School of Medicine, La Jolla, USA26Children?s Hospital of Philadelphia, Philadelphia, USA27Boston Children?s Hospital (BCH), Boston, USA28University of Minnesota, Minneapolis, USA29Kennedy Krieger Institute, Baltimore, USA30Oregon Health & Science University, Portland, USA31University of Minnesota, Minneapolis, USA32University of Colorado School of Medicine, Aurora, USA33Department of Health Psychology, University of Missouri, Columbia, USA34Thompson Center for Autism and Neurodevelopmental Disorders, University of Missouri, Columbia, USA35Geisinger Autism & Developmental Medicine Institute, Lewisburg, USA36Southwest Autism Research and Resource Center, Phoenix, USA

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • Cortex development
  • Gene families
  • Neurodevelopmental disorders
  • hnRNPs

PubMed: MeSH publication types

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

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