Jeffries, Lauren;
Mis, Emily K;
McWalter, Kirsty;
Donkervoort, Sandra;
Brodsky, Nina N;
Carpier, Jean-Marie;
Ji, Weizhen;
... Lakhani, Saquib A; + view all
(2024)
Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections.
Genetics Medecine
, 26
(2)
, Article 101023. 10.1016/j.gim.2023.101023.
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Abstract
PURPOSE: We sought to delineate a multisystem disorder caused by recessive CRELD1 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 one 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 to 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 as compared to healthy donors. CONCLUSION: This patient cohort combined with experimental data provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1.
| Type: | Article |
|---|---|
| Title: | Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.gim.2023.101023 |
| Publisher version: | https://doi.org/10.1016/j.gim.2023.101023 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | CRELD1, developmental delay, epilepsy, hypotonia |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10183303 |
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