Ectodermal dysplasia

Gene: MSX1

Green List (high evidence)

Comment on mode of inheritance: There are 3 unrelated pedigrees reported in literature where affected individuals presented with tooth agenesis and/or nail dysplasia, harbouring biallelic variants in MSX1. However, the c*6C>T variant (present in 2/3 cases) is too common to cause a Mendelian disorder. In addition, all 3 studies used direct MSX1 sequencing. As such, the influence of other genes cannot be excluded. Due to scarce and conflicting evidence for recessive Ectodermal dysplasia, the MOI should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.

Created: 12 Feb 2026, 5:21 p.m. | Last Modified: 12 Feb 2026, 5:21 p.m.

Panel Version: 4.21

BIALLELIC CASE REPORTS:
PMID: 25565750 Ceyhan et al., 2014
Report of Turkish cases with non-syndromic tooth agenesis and other dental anomalies: 5 heterozygotes and 1 homozygote; MSX1 variants reported: c.119C>G, p.Ala40Gly; c.347C>T, p.(Gly116Gly); c.463C>A, p.(Pro155Glu); c.95C>T, p.(Ala32Val); c*6C>T (3' UTR region, homozygous).
c*6C>T is common in population (MAF = 0.3962 in gnomAD, with total of 41187 homozygotes reported).
Only MSX1 was sequenced in all patients.

PMID: 24031111 Ghaderi et al., 2013
Case report - 2.5-year-old boy with early exfoliation of the primary canine, absence of the primary incisors, and nail dysplasia (Witkop syndrome). Homozygous mutation was identified in 3'-UTR of MSX1 of proband (*6C>T), het parents unaffected. Analysed two coding exons, exon-intron boundaries, and part of 3’-UTR of MSX1 only.

PMID: 16932841 Chishti et al., 2006
2 distantly related Pakistani pedigrees with recessive mutation p.Ala219Thr (?), segregating with oligodontia and other dental anomalies. Method: linkage analysis in the pedigree followed by direct MSX1 sequencing.

MSX1 is associated with 3 autosomal dominant disease entities in OMIM: Ectodermal dysplasia 3, Witkop type, 189500; Orofacial cleft 5, 608874; Tooth agenesis, selective, 1, with or without orofacial cleft, 106600 (OMIM accessed 12th Feb 2026).

ClinGen Expert Panels have classified the link between MSX1 and AD tooth agenesis, selective, 1 as Definitive (Feb 2024), but AD tooth and nail syndrome has been classified as Disputed (Oct 2023).

Created: 12 Feb 2026, 5:05 p.m. | Last Modified: 12 Feb 2026, 5:16 p.m.

Panel Version: 4.21

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Ectodermal dysplasia 3, Witkop type, OMIM:189500; Tooth agenesis, selective, 1, with or without orofacial cleft, OMIM:106600

Publications

• 16932841
• 24031111
• 25565750

Comment when marking as ready: Associated with phenotype in OMIM, not in G2P. Two variants reported in Ectodermal dysplasia 3, Witkop type 189500. Msx1-null mice exhibit tooth agenesis and defective nail plates (PMID 11369996)

Created: 15 Aug 2016, 7:02 a.m.

Comment on phenotypes: Variants also reported in Orofacial cleft 5 608874 and Tooth agenesis, selective, 1, with or without orofacial cleft 106600

Created: 10 Aug 2016, 10:20 a.m.

Comment on mode of inheritance: PMID 24031111 reports biallelic inheritance

Created: 10 Aug 2016, 9:49 a.m.

Green List (high evidence)

Ok to include for Witkop syndrome

Created: 19 Nov 2015, 3:06 p.m.

Phenotypes
Witkop syndrome