Epidermolysis bullosa and congenital skin fragility

Gene: ATP2A2

Green List (high evidence)

Comment on list classification: There are numerous patients reported in literature with monoallelic LoF germline variants in ATP2A2 causing Darier disease. Darier disease is characterized by warty papules and plaques in seborrheic areas, palmoplantar pits, and distinctive nail abnormalities (PMID: 10080178). The age of onset is usually in adolescence. Based on the available evidence, this gene should be updated to Green on Epidermolysis bullosa and congenital skin fragility. As per internal communication with Veronica Kinsler, this is the closest Dermatology panel fit at this time.

Created: 13 Nov 2025, 11:11 a.m. | Last Modified: 6 Jan 2026, 10:30 a.m.

Panel Version: 2.10

PMID: 38536168 Atzmony et al., 2024
9 patients with Darier disease (DD) from (presumed) unrelated families with heterozygous pathogenic germline LoF variants in ATP2A2. 8/9 patients had family history of DD. Age ranged from 40 to 69 years on enrollment. 8/9 individuals had classic disease distribution with hyperkeratotic papules and plaques over seborrheic areas and v-shaped notching of the nails. One patient had comedonal DD, manifested over forehead, cheeks and trunk.
Variants detected in ATP2A2 - none of which are present in gnomAD v4.1.0.:
c.1000C>T, p.Arg334X
c.1582C>T, p.Arg528X
c.2256_2256Dup, p.(Tyr753Leufs*60)
c.1406_1415del, p.(Asn469Thrfs*7)
c.530A>C, p.Gln177Pro (recurring, 3/9 families)
c.395A>C, p.Gln132Pro; c.392G>T, p. Arg131Leu - detected in cis in patient DD5
c.1327 A>C, p.Thr443Pro
Patients with persistent lesions had additional somatic variants in ATP2A2, while individuals with a 'wax and wane' skin presentation did not.

Many other cases of ATP2A2-related Darier disease have been reported in literature:
PMID: 10080178 Sakuntabhai et al., 1999 - 8 unrelated British families and 5 sporadic cases with DD
PMID: 10441325 Jacobsen et al., 1999 - 19 unrelated DD patients with 17 mutations detected in ATP2A2 + link to neuropsychiatric phenotypes
PMID: 35283639 Hagino et al., 2022 - 34-year-old Japanese woman with familial DD, het for c.616A>C (p.Asn206His) in ATP2A2
PMID: 38791022 Frustaci et al., 2024 - 62-year-old female (DD onset at 9yo), developed cardiac symptoms at 60yo, heterozygous for ATP2A2 c.118G>A

This gene is associated with AD Darier disease, OMIM:124200 and Acrokeratosis verruciformis, OMIM:101900 (accessed 13th Nov 2025).

Created: 13 Nov 2025, 11:06 a.m. | Last Modified: 13 Nov 2025, 11:14 a.m.

Panel Version: 2.7

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Darier disease, OMIM:124200; Acrokeratosis verruciformis, OMIM:101900; Darier disease, MONDO:0007417; acrokeratosis verruciformis, MONDO:0007048

Publications

• 10080178
• 10441325
• 35283639
• 38791022
• 38536168

Green List (high evidence)

This status as amber must have been an oversight

Created: 31 Oct 2025, 1:56 p.m. | Last Modified: 31 Oct 2025, 1:56 p.m.

Panel Version: 2.7

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Darier disease

Publications

• PMID: 10080178

I don't know

This gene was part of a gene list collated by John McGrath, KCL and Veronica Kinsler, UCL, 17.Jun.2019 on behalf of the GMS Skin Specialist Test Group. Gene Symbol submitted:ATP2A2; Suggested initial gene rating: Green; Evidence for inclusion: none provided; Evidence for exclusion: none provided; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none provided.

Created: 9 Sep 2019, 3:38 p.m. | Last Modified: 9 Sep 2019, 3:38 p.m.

Panel Version: 0.15