CLTC (17q23.1) · Clathrin Heavy Chain · Autosomal dominant, de novo · Prepared from published case series (n ≈ 75) and ClinVar / gnomAD data. For case conferences and referral letters; not a substitute for specialist interpretation.
| Clinical Feature | Overall Prevalence† | Missense Variants (n≈45) | Truncating Variants (n≈30) |
|---|---|---|---|
| Intellectual Disability | ~100% | Mild to Severe (variable) | Typically Mild to Moderate |
| Speech / Language Delay | ~100% | Universal; often severe | Universal; variable severity |
| Developmental / Motor Delay | ~90% | Significant hypotonia and delay | Mild to moderate hypotonia |
| Epilepsy / Seizures | ~60% | ~80% of missense cases; early onset | ~20% of truncating cases; later onset |
| Behavioral Features | ~60% | Autistic traits, stereotypies | ADHD, specific learning disorders |
| Microcephaly | ~50% | More common (~50% of missense) | Less common; seen in subset |
| Feeding Difficulties | ~40% | Particularly during infancy | Variable; less frequently reported |
† Prevalence estimates from published CLTC case series and registries (aggregated cohort n ≈ 75).[1][2]
| Method | Estimated Rate | Interpretation |
|---|---|---|
| ClinVar (Method 1) | 1 in 424,000 | Diagnosed floor — US clinical submissions only |
| gnomAD Constraint (Method 2) | ~1 in 35,000 | Biological estimate ★ — gene constraint model, independent of diagnosis rate |
| Fermi Estimation (Method 3) | ~1 in 38,000 | Independent cross-check — de novo mutation rate × penetrance |
Sources: ClinVar (ncbi.nlm.nih.gov/clinvar); gnomAD v2.1[3] — Karczewski KJ et al. Nature. 2020;581:434–443; de novo rate methodology — McRae JF et al. Nature. 2017;542:433–438.[4]
| Type | Molecular consequence | Severity tendency | Mechanism | ~% ClinVar |
|---|---|---|---|---|
| Missense | Amino-acid substitution; protein produced but misfolded | Typically most severe | Dominant-negative | ~45% |
| Nonsense | Premature stop codon; truncated fragment degraded | Loss-of-function (milder) | Haploinsufficiency | ~18% |
| Frameshift | Reading-frame shift → premature stop | Loss-of-function (milder) | Haploinsufficiency | ~16% |
| Splice-site | Disrupts exon–intron boundary; exon skipping / intron retention | Loss-of-function (milder) | Haploinsufficiency | ~13% |
| Silent | Synonymous change; protein identical (rarely disrupts splicing) | Generally minimal | Variable | ~8% |
ClinVar percentages are approximate, based on pathogenic/likely pathogenic CLTC submissions (accessed 2026).[1]
Dominant-negative vs haploinsufficiency
Missense variants produce a structurally altered clathrin heavy chain that poisons the triskelion network (dominant-negative effect), explaining the more severe phenotype compared with truncating variants, which simply halve functional clathrin supply (haploinsufficiency).[1]
Diagnostic gap
Published literature documents ~31 cases; ClinVar holds ~199 effective pathogenic variants; gnomAD and Fermi estimates converge on ~1 in 35,000–38,000 live births — comparable to STXBP1 and SCN1A-related Dravet syndrome. Most CLTC-ID individuals worldwide remain undiagnosed.[3]
gnomAD constraint (CLTC)
pLI = 1.00 · LOEUF = 0.12 · o/e missense = 0.73. The near-zero LOEUF confirms extreme intolerance to loss-of-function variants — among the strongest constraint scores in the genome.[3]
| Area | Watch for | Recommended action |
|---|---|---|
| Brain development | Microcephaly, corpus callosum hypoplasia, cortical malformations | Serial OFC and brain MRI at diagnosis or when growth deviates. |
| Epilepsy / EEG | Focal or generalised seizures; especially missense variants or onset before age 2 | Baseline EEG; repeat with any paroxysmal event or developmental regression. |
| Kidney structure | Hyperechogenic kidneys, agenesis, vesicoureteral reflux | Renal ultrasound at diagnosis; nephrology referral if anomalies present. |
| Newborn signs | Hypotonia ('floppy baby'), inguinal or umbilical hernia | Document tone exam; surgical referral for hernias; early-intervention referral. |
| Feeding / growth | Poor suck, slow weight gain, intrauterine or postnatal growth restriction | Growth chart tracking; SLP or feeding-team review; GI if persistent. |
Prenatal ultrasound red flags
Hypoplastic or absent corpus callosum
Best assessed on dedicated mid-sagittal views; correlate with biparietal diameter.
Ventriculomegaly
Atrial width ≥10 mm warrants follow-up imaging and consideration of single-gene causes.
Microcephaly / small biparietal diameter
Plot serial biometry; flag persistent <3rd centile for genetic review.
Cerebellar or posterior fossa anomalies
Assess vermis, cisterna magna, and brainstem on axial and sagittal planes.
Intrauterine growth restriction (IUGR)
Consider when paired with CNS findings rather than as an isolated sign.
When these findings cluster on a high-resolution second-trimester scan and a single-gene cause is plausible, offer trio whole-exome sequencing or a fetal neurodevelopmental disorder panel that includes CLTC.[5]
Adult-onset parkinsonism flag
A small but documented late-teens / early-twenties onset of bradykinesia, rigidity, and asymmetric tremor has been reported in adult CLTC carriers. Long-term follow-up should include a brief movement-disorder review. Treatment guidance is out of scope here.[6][7]
Recurrence-risk counseling
Most CLTC variants arise de novo; sibling recurrence is very low but not zero due to parental germline mosaicism. Test both parents for the proband’s variant using deep-coverage NGS (not Sanger alone) before counseling future pregnancies.[8]
Recommended diagnostic test
Trio whole-exome sequencing (or a large ID/epilepsy gene panel explicitly including CLTC) is highest-yield first-line. CMA is typically negative (single nucleotide variants / small indels). Confirm candidate variants by Sanger and report in HGVS on canonical transcript NM_004859.[1][2]
ClinVar
Clinical significance, ACMG classification, and submitter evidence for reported CLTC variants.
https://www.ncbi.nlm.nih.gov/clinvar/?term=CLTC%5BGene%5D
gnomAD
Population allele frequency, constraint metrics (pLI, LOEUF), and observed-vs-expected variant counts.
https://gnomad.broadinstitute.org/gene/ENSG00000141367
Decipher
Clinical information, phenotype data, and developmental-disorder context curated for CLTC.
https://www.deciphergenomics.org/gene/CLTC/overview/clinical-info
This summary is an educational reference derived from published CLTC case series, ClinVar, and gnomAD. Individual presentations vary significantly. It is not a substitute for advice from a clinical geneticist or specialist. Source pages: cltc-portal /clinician · /incidence.
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.
Karczewski KJ, Francioli LC, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–443. (gnomAD v2.1 CLTC gene constraint scores: pLI = 1.00, LOEUF = 0.12.) gnomAD Browser: gnomad.broadinstitute.org/gene/ENSG00000141367
McRae JF, Clayton S, Fitzgerald TW, et al. (Deciphering Developmental Disorders Study). Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542(7642):433–438. (Methodological basis for de novo mutation rate estimation used in the Fermi incidence model.)
Shen Y, et al. A novel de novo CLTC variant altering RNA splicing causes fetal developmental abnormalities. BMC Med Genomics. 2023;16:341. (Supports prenatal ultrasound red-flag findings and recommendation for trio WES or ID/epilepsy panel.)
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):1430–1432.
Usnich T, et al. Correspondence on levodopa response in CLTC-related parkinsonism. Mov Disord Clin Pract. 2024.
Sveistrup & Myers, et al. Mosaic CLTC pathogenic variant causing focal epilepsy with normal intelligence. Epileptic Disord. 2024 Dec;26(6):875.