Key milestones in the discovery, genetic characterisation, and clinical understanding of CLTC-related disorders.
The human clathrin heavy chain gene (CLTC) was first cloned and chromosomally mapped (reported as 17q11-qter, later refined to 17q23.1), establishing the foundation for future genetic research.[1]
Early animal models demonstrate the critical role of clathrin-mediated endocytosis in synaptic vesicle recycling and neurological development.[2]
De novo variants in CLTC are first reported in the literature as a cause of a distinct neurodevelopmental syndrome characterised by intellectual disability and epilepsy.[3]
A comprehensive review establishes the distinct phenotypic differences between missense variants (often more severe, with epilepsy) and truncating variants.[4]
Global patient registries like GenomeConnect see increased enrollment, facilitating natural history studies and paving the way for future therapeutic research.[5]
References
Dodge GR, Kovalszky I, McBride OW, Yi HF, Chu ML, Saitta B, Stokes DG, Iozzo RV. Human clathrin heavy chain (CLTC): partial molecular cloning, expression, and mapping of the gene to human chromosome 17q11-qter. Genomics. 1991;11(1):174–178. (Original primary cloning and chromosomal mapping of the human CLTC gene; the locus was reported as 17q11-qter at the mapping resolution available in 1991 and has since been refined to 17q23.1 in modern databases such as OMIM #118955.)
Blondeau F, Ritter B, Allaire PD, Wasiak S, Girard M, Hussain NK, Angers A, Legendre-Guillemin V, Roy L, Boismenu D, Kearney RE, Bell AW, Bergeron JJM, McPherson PS. Tandem MS analysis of brain clathrin-coated vesicles reveals their critical involvement in synaptic vesicle recycling. Proc Natl Acad Sci U S A. 2004;101(11):3833–3838. (Seminal 2004 study directly establishing the critical role of clathrin-coated vesicles in synaptic vesicle recycling in the brain.)
DeMari J, Mroske C, et al. CLTC as a clinically novel gene associated with multiple malformations and developmental delay. Am J Med Genet A. 2016;170(4):958–966. (First major report of de novo CLTC variants as a cause of a distinct neurodevelopmental syndrome.)
Nabais Sá MJ, de Man SA, et al. De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy. Genet Med. 2020;22(4):797–802. (Comprehensive genotype-phenotype correlation study establishing the missense vs. truncating severity distinction.)
Sveistrup & Myers, et al. Mosaic CLTC pathogenic variant causing focal epilepsy with normal intelligence. Epileptic Disord. 2024 Dec;26(6):875. (Published alongside increasing patient registry enrollment, demonstrating the expanding phenotypic and clinical understanding of CLTC-ID.)