Childhood onset hereditary spastic paraplegia

Gene: TYW1

I don't know

Comment on list classification: There is one pedigree reported in literature linking biallelic TYW1 variants to cerebral palsy with intellectual disability. There is also good functional evidence in zebrafish, mouse, and human brain organoids supporting TYW1 role in motor function and cognition. Based on available evidence, this gene can only be rated Amber for now.

Created: 17 Mar 2026, 12:47 p.m. | Last Modified: 17 Mar 2026, 12:47 p.m.

Panel Version: 8.39

PMID: 34077496 Li et al., 2021
2 Chinese sibs (non-consanguineous parents) reported with comp het TYW1 variants: NM_018264: c.616C>T, p.R206C & c.1166G>A, p. R389Q.
Proband CP_012_1, male - Wechsler Preschool and Primary Scale of Intelligence IQ = 40 at 7 years old (moderate ID);
CP_012_2, older sister - diagnosed with mixed type cerebral palsy (spasticity, dyskinesia), IQ <50 (moderate ID).
Parents confirmed heterozygous for 1 variant each. TYW1:c.616C>T - MAF in gnomADv4 = 0.0004900, including 1 homozygote. TYW1:c.1166G>A MAF in gnomAD v4 = 0.0001559, no homozygotes.

Functional evidence: TYW1 protein levels dramatically reduced in proband compared to controls; tyw1 deficiency in zebrafish resulted in ectopic neuronal cell migration in the brain and undifferentiated motor neuronal cells in the spinal cord - this was rescued by WT human and zebrafish tyw1 mRNA, but not by mRNA with patients' mutations. In addition, tyw1 knockdown zebrafish showed recuded swimming capacity. Kncokout tyw1-/- mice showed impaired motor function and reduced cognition in behavioural tests.

PMID: 38706838 Sun et al., 2024
Fucntional evidence: Study used brain organoid model and human embryonic stem cells to show that translation efficiency of UUU codon was compromised in TYW1−/− cells. Also, neuron differentiation was impaired when TYW1 was depleted.

TYW1 is not yet associated with a phenotype in OMIM, ClinGen or G2P (accessed 17 Mar 2026).
Sources: Literature

Created: 17 Mar 2026, 12:44 p.m. | Last Modified: 17 Mar 2026, 12:49 p.m.

Panel Version: 8.39

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
cerebral palsy, MONDO:0006497

Publications

• 34077496