Amelogenesis imperfecta

Gene: TUFT1

Comment on list classification: As reviewed by Claire Smith, variants in TUFT1 are not associates with dental abnormalities. Instead, 11 individuals from 4 families with biallelic variants in TUFT1 presented with woolly hair and skin fragility. Based on the available evidence, TUFT1 should remain Red for Amelogenesis imperfecta.

Created: 7 Nov 2025, 5:09 p.m. | Last Modified: 7 Nov 2025, 5:09 p.m.

Panel Version: 4.16

PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted. WES identified a homozygous splice acceptor site variant in intron 8, c.724-2A>G in TUFT1.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).

Created: 7 Nov 2025, 5:05 p.m. | Last Modified: 7 Nov 2025, 5:15 p.m.

Panel Version: 4.19

Phenotypes
Woolly hair-skin fragility syndrome, OMIM:620415

Publications

• 25531160
• 36689522
• 37716648

Red List (low evidence)

Publication identified homozygous predicted loss-of-function tuftelin-1 (TUFT1) variants in nine individuals, from three families, with woolly hair and skin fragility. One donor splice-site variant, c.60+1G>A, was present in two families, while a frameshift variant, p.Gln189Asnfs*49, was found in the third family

Publication explicitly states that individuals did not have a dental disease phenotype. It may be that specific types of variants in this gene may cause dental disease (? remains to be seen), but it's suggestive that these variants are not like to include LoF variants from the findings in this paper. Article corresponding author is McGrath, who has previously identified dental phenotypes in other types of skin disease (Epidermolysis bullosa), so it seems unlikely that a dental phenotype has been overlooked here as is sometimes the case.

Variants were identified through whole-genome sequencing performed as part of the 100KGP and whole-exome sequencing (WES) performed using standard methods for patients recruited through NHS GLH. Panel-agnostic analysis on WGS data was performed.

Created: 14 Jul 2025, 11:08 a.m. | Last Modified: 14 Jul 2025, 11:08 a.m.

Panel Version: 4.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
woolly hair; skin fragility; keratosis pilaris

Publications

• 36689522

Publications

• 25531160