Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections

Deciphering Developmental Disorders, Genomics England Research Consortium, Undiagnosed Disease Network, Lauren Jeffries, Emily K. Mis, Kirsty McWalter, Sandra Donkervoort, Nina N. Brodsky, Jean Marie Carpier, Weizhen Ji, Cristian Ionita, Bhaskar Roy, Jon S. Morrow, Armine Darbinyan, Krishna Iyer, Ritu B. Aul, Siddharth Banka, Katherine R. Chao, Laura Cobbold, Stacey CohenHelena M. Custodio, Margaret Drummond-Borg, Frances Elmslie, Erika Finanger, Bryan E. Hainline, Ingo Helbig, Stacy Hewson, Ying Hu, Adam Jackson, Dragana Josifova, Monica Konstantino, Meganne E. Leach, Bryan Mak, David McCormick, Elisabeth McGee, Stanley Nelson, Joanne Nguyen, Kimberly Nugent, Lucy Ortega, Howard P. Goodkin, Elizabeth Roeder, Sani Roy, Katie Sapp, Dimah Saade, Sanjay M. Sisodiya, Karen Stals, Shelley Towner, William Wilson, Silvia Borras, Caroline Clark, John Dean, Zosia Miedzybrodzka, Alison Ross, Stephen Tennant, Tabib Dabir, Deirdre Donnelly, Mervyn Humphreys, Alex Magee, Vivienne McConnell, Shane McKee, Susan McNerlan, Patrick J. Morrison, Gillian Rea, Fiona Stewart, Trevor Cole, Nicola Cooper, Lisa Cooper-Charles, Helen Cox, Lily Islam, Joanna Jarvis, Rebecca Keelagher, Derek Lim, Dominic McMullan, Jenny Morton, Swati Naik, Mary O'Driscoll, Kai Ren Ong, Deborah Osio, Nicola Ragge, Sarah Turton, Julie Vogt, Denise Williams, Simon Bodek, Alan Donaldson, Alison Hills, Karen Low, Ruth Newbury-Ecob, Andrew M. Norman, Eileen Roberts, Ingrid Scurr, Sarah Smithson, Madeleine Tooley, Steve Abbs, Ruth Armstrong, Carolyn Dunn, Simon Holden, Soo Mi Park, Joan Paterson, Lucy Raymond, Evan Reid, Richard Sandford, Ingrid Simonic, Marc Tischkowitz, Geoff Woods, Lisa Bradley, Joanne Comerford, Andrew Green, Sally Lynch, Shirley McQuaid, Brendan Mullaney, Jonathan Berg, David Goudie, Eleni Mavrak, Joanne McLean, Catherine McWilliam, Eleanor Reavey, Tara Azam, Elaine Cleary, Andrew Jackson, Wayne Lam, Anne Lampe, David Moore, Mary Porteous, Emma Baple, Júlia Baptista, Carole Brewer, Bruce Castle, Emma Kivuva, Martina Owens, Julia Rankin, Charles Shaw-Smith, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Therese Bradley, Rosemarie Davidson, Carol Gardiner, Shelagh Joss, Esther Kinning, Cheryl Longman, Ruth McGowan, Victoria Murday, Daniela Pilz, Edward Tobias, Margo Whiteford, Nicola Williams, Angela Barnicoat, Emma Clement, Francesca Faravelli, Jane Hurst, Lucy Jenkins, Wendy Jones, V. K. Ajith Kumar, Melissa Lees, Sam Loughlin, Alison Male, Deborah Morrogh, Elisabeth Rosser, Richard Scott, Louise Wilson, Ana Beleza, Charu Deshpande, Frances Flinter, Muriel Holder, Melita Irving, Louise Izatt, Shehla Mohammed, Aneta Molenda, Leema Robert, Wendy Roworth, Deborah Ruddy, Mina Ryten, Shu Yau, Christopher Bennett, Moira Blyth, Jennifer Campbell, Andrea Coates, Angus Dobbie, Sarah Hewitt, Emma Hobson, Eilidh Jackson, Rosalyn Jewell, Alison Kraus, Katrina Prescott, Eamonn Sheridan, Jenny Thomson, Kirsty Bradshaw, Abhijit Dixit, Jacqueline Eason, Rebecca Haines, Rachel Harrison, Stacey Mutch, Ajoy Sarkar, Claire Searle, Nora Shannon, Abid Sharif, Dustin Baldridge, F. Sessions Cole, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Jennifer Wambach

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Purpose: We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor–like domains 1 (CRELD1) gene variants. Methods: The impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells. Results: Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with 1 recurrent variant, p.(Cys192Tyr), identified in 10 families. X tropicalis tadpoles with creld1 knockdown displayed developmental defects along with increased susceptibility to induced seizures compared with controls. Additionally, human CRELD1 harboring missense variants from affected individuals had reduced protein function, indicated by a diminished ability to induce craniofacial defects when overexpressed in X tropicalis. Finally, baseline analyses of peripheral blood mononuclear cells showed similar proportions of immune cell subtypes in patients compared with healthy donors. Conclusion: This patient cohort, combined with experimental data, provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1.

Original languageEnglish
Article number101023
JournalGenetics in Medicine
Volume26
Issue number2
DOIs
StatePublished - Feb 2024

Keywords

  • CRELD1
  • Cardiac arrythmia
  • Developmental delay
  • Epilepsy
  • Hypotonia

Fingerprint

Dive into the research topics of 'Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections'. Together they form a unique fingerprint.

Cite this