WNT10A F228I - GET-Evidence


WNT10A F228I

(WNT10A Phe228Ile)

Short summary

Causes ectodermal dysplasia in a recessive manner (malformations of teeth and nails, abnormal/loss of sweating). Although reports have high statistical significance, allele frequency for this variant is high relative to the incidence of the disease. This suggests it may be milder than other pathogenic variants and cause disease with less than 100% penetrance and/or that the disease is more common than reported. Bohring et al. report heterozygotes for pathogenic variants in this gene often have milder skin, tooth, and nail abnormalities, with males having a higher rate of tooth abnormalities.

Variant evidence
Computational 2

Other variants in the gene associated with causing symptoms, Polyphen 2 predicts damaging effect.

Functional -
Case/Control 5

Very strong significance, mostly due to results of Cluzeau et al.

See Bohring A et al. 2009 (19559398), Cluzeau C et al. 2011 (20979233).

Familial 1

LOD = 0.62

See Cluzeau C et al. 2011 (20979233).

Clinical importance
Severity 3
Treatability 1
Penetrance 5


Moderate clinical importance, pathogenic

(The "moderate clinical importance, " qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary

Observations reported by Cluzeau et al. establish high significance for enrichment of the variant in cases. However, the allele frequencies seen in EVS data and 1000 Genomes data (1.9% and 1.0%) are so high that they imply 1 to 4 out of 10,000 individuals are homozygous for this variant. This seems to contradict rarity of the disease.

This review of Ectodermal dysplasia by Shah et al.: http://emedicine.medscape.com/article/1110595-overview estimates ectodermal dysplasia has a collective prevalence of 7 out of 10,000. If this number is correct and if WNT10A-F228I caused the disease with 100% penetrance when homozygous, it would imply 10%-50% of patients with ectodermal dysplasia are WNT10A-F228I homozygotes (and presumably much or most of other cases would be heterozygous). In contrast with this prediction, Cluzeau et al. only found 2 out of 63 patients homozygous (3%) and 8 heterozygous (13%). This suggests either ectodermal dysplasia is more common that Shah et al. report, or this variant is not causing the disease with 100% penetrance (possibly both are true).

Allele frequency

  • A @ chr2:219755011: 1.9% (202/10750) in EVS
  • A @ chr2:219463254: 1.6% (2/128) in GET-Evidence
  • Frequency shown in summary reports: 1.9% (202/10750)


Bohring A, Stamm T, Spaich C, Haase C, Spree K, Hehr U, Hoffmann M, Ledig S, Sel S, Wieacker P, Röpke A. WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex-biased manifestation pattern in heterozygotes. Am J Hum Genet. 2009 Jul;85(1):97-105. Epub 2009 Jun 25. PubMed PMID: 19559398; PubMed Central PMCID: PMC2706962.

A screen of mutations in 123 families with ectodermal dysplasia or isolated severe oligodontia. 11 had mutations in WNT10A, 4 of which were homozygous or compound heterezoygous for this variant (two of each). This variant was also seen in 2 out of 396 control chromosomes. Counting alleles, this is case+: 6, case-: 240, control+: 2, control-: 394. This has p = 0.059.

54% of heterozygotes are reported to have some mild symptoms similar to homozygotes, including: a few missing permanent teeth, nail dystrophy, dry skin, thickened palm/sole skin, or sparse hair, eyebrows, or eyelashes. Males had a higher incidence of tooth anomalies.

Calculating LOD score: Pedigrees for the four families (073, 112, 122, 123) is in figure 1. Not counting probands, the genotypes of 5 proband siblings predicts their phenotype (in all cases unaffected heterozygotes or non-carriers), each has a 75% chance of happening randomly. LOD = log10 ( 1 / ( .75**5)) = 0.62.

Cluzeau C, Hadj-Rabia S, Jambou M, Mansour S, Guigue P, Masmoudi S, Bal E, Chassaing N, Vincent MC, Viot G, Clauss F, Manière MC, Toupenay S, Le Merrer M, Lyonnet S, Cormier-Daire V, Amiel J, Faivre L, de Prost Y, Munnich A, Bonnefont JP, Bodemer C, Smahi A. Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. Hum Mutat. 2011 Jan;32(1):70-2. PubMed PMID: 20979233.

In a screen of 65 hypohidrotic/anhidrotic (abnormally low or absent sweating) ectodermal dysplasia cases, 14 had mutations in WNT10A � 10 of these were carriers of F228I (two homozygous, eight heterozygous or compound heterozygous). The variant was not seen in 150 control chromosomes. Counting alleles: case+: 12, case-: 118, control+: 0, control-: 150. This is p = 7.5 * 10^-5.

Using EVS5400 data as controls (202 out of 10750 alleles) significance is similarly strong (p = 9 * 10^-6).


GS06994 - var-GS06994-1100-36-ASM
het A @ chr2:219463255


Other external references

  • Score: 0.997 (probably damaging)

Other in silico analyses

  • NBLOSUM100 score = 2
  • GET-Evidence autoscore = 4

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Gene search

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