The following is a summary of “Persistent Cutaneous Lesions of Darier Disease and Second-Hit Somatic Variants in ATP2A2 Gene,” published in the March 2024 issue of Dermatology by Atzmony, et al.
Darier disease (DD) is a rare genetic skin disorder caused by heterozygous variants in the ATP2A2 gene. Clinically, it presents with recurrent hyperkeratotic papules and plaques, predominantly in seborrheic areas. While some lesions fluctuate with environmental factors, others are severe and resistant to therapy. For a study, researchers sought to investigate the molecular mechanisms behind the persistence of skin lesions in DD.
The study involved extracting DNA from unaffected skin, transient and persistent lesional skin, and blood from 9 patients with DD. Genetic analysis was conducted using paired-whole exome sequencing of affected skin and blood or deep sequencing of ATP2A2 from affected skin. Chromosomal microarray analysis was performed to detect copy number variants and loss of heterozygosity. All variants were validated by Sanger sequencing or restriction fragment length polymorphism. Paired whole-exome sequencing and deep sequencing of the ATP2A2 gene were performed on blood and skin samples from persistent and transient lesions and unaffected skin in patients with DD. The study focused on identifying germline and somatic genomic characteristics of persistent and transient cutaneous lesions in DD.
All 9 patients had heterozygous pathogenic germline variants in the ATP2A2 gene, with 6 females. Participants’ ages ranged from 40 to 69 years. All 11 persistent lesions were associated with second-hit somatic variants in the ATP2A2 gene. These somatic variants were deemed highly deleterious based on combined annotation-dependent depletion (CADD) scores or affected splicing, with 3 previously reported in DD and acrokeratosis verruciformis of Hopf. No second-hit variants were found in transient lesions (n=2) or normal skin (n=2).
The study found persistent DD lesions were linked to second-hit somatic variants in the ATP2A2 gene. Identifying these second-hit variants provides critical insights into the mechanisms contributing to their persistence.
Reference: jamanetwork.com/journals/jamadermatology/article-abstract/2816454
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