Observed clinical correlations between specific variant types (missense vs. truncating) and phenotype severity, with workup, counseling, and lookup guidance.
| Feature | Missense | Truncating (LoF) |
|---|---|---|
| Intellectual Disability | Mild to Severe (variable) | Typically Mild to Moderate |
| Speech / Language Delay | Universal; often severe | Universal; variable severity |
| Developmental / Motor Delay | Significant hypotonia and delay | Mild to moderate hypotonia |
| Epilepsy / Seizures | ~80% of missense cases; early onset | ~20% of truncating cases; later onset |
| Behavioral Features | Autistic traits, stereotypies | ADHD, specific learning disorders |
| Microcephaly | More common (~50% of missense) | Less common; seen in subset |
| Feeding Difficulties | Particularly during infancy | Variable; less frequently reported |
A full-length but misshapen heavy chain joins normal triskelions and disrupts the assembled clathrin coat — a effect that impairs function well beyond what halving the dose would predict. This group is enriched for early-onset epilepsy, microcephaly, and corpus callosum hypoplasia.
Premature termination codons are usually cleared by nonsense-mediated decay, leaving roughly 50% functional CHC1 — classical . Phenotypes cluster toward the milder end of the developmental spectrum, with lower seizure rates than the missense group.
References
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.
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.
Kusick GF, et al. The recurrent pathogenic Pro890Leu substitution in CLTC causes a generalized defect in synaptic transmission in Caenorhabditis elegans. Front Mol Neurosci. 2023;16:1170061.
Shen Y, et al. A novel de novo CLTC variant altering RNA splicing causes fetal developmental abnormalities. BMC Med Genomics. 2023;16:341.
Sveistrup & Myers, et al. Mosaic CLTC pathogenic variant causing focal epilepsy with normal intelligence. Epileptic Disord. 2024 Dec;26(6):875.
Nardecchia F, et al. Improvement of movement disorder and neurodevelopment under selegiline in a CLTC-deficient patient. Mov Disord Clin Pract. 2023 Sep;10(9):1395–1399.
Usnich T, et al. Correspondence on levodopa response in CLTC-related parkinsonism. Mov Disord Clin Pract. 2024.
Nardecchia F, et al. Author reply on CLTC-related parkinsonism (correspondence). Mov Disord Clin Pract. 2024.