Persistent Darier disease lesions contain second-hit somatic gene variants

Key takeaways:

• Variants of the ATP2A2 gene were found in persistent Darier disease lesions.
• Patients with transient lesions did not have second-hit variants of the gene.

Second-hit somatic variants in the ATP2A2 gene were associated with persistent Darier disease lesions, according to a case series study.

“Darier disease (DD) is a rare genetic skin disease caused by heterozygous loss of function (LOF) variants in the ATP2A2 gene, encoding the sarcoplasmic reticulum calcium ATPase pump, SERCA2,” Lihi Atzmony, MD, of the division of dermatology at Rabin Medical Center, Petah Tikva, Israel, and colleagues wrote. “DD has a wide phenotypic presentation involving skin, mucous membranes and nails. ... In this prospective case series study, we aimed to identify the molecular mechanism that differentiates persistent from transient DD skin lesions.”

In nine included patients (age range, 40-69 years; six women), less severe lesions that responded to therapy during follow-up, leaving normal or dyspigmented skin, were defined as transient, whereas lesions with thick, keratotic papules and plaques with or without erosions, AKV-like lesions and plaques seeded with comedos and isolated comedos were classified as persistent. Persistent lesions also had not improved with topical antibiotic or steroid treatments and had not waxed or waned in the previous 2 years.

All lesions were photographed before and after recurrence.

Whole-exome sequencing (WES) and DNA analysis were performed on blood from each subject, as well as two transient and 11 persistent lesions, and normal skin of two patients.

Germline and second-hit somatic variants of the ATP2A2 gene, all variants in Genome Aggegation Database gnomAD), were found in the blood and tissue samples from all six patients with persistent lesions. In two patient who each had two distinct persistent lesions, different variants of the gene were found in different lesions in the same patient.

Of those found, the second-hit somatic variants were classified as highly deleterious or highly deleterious based on affect splicing or combined annotation-dependent depletion scores..

In two patients with transient lesions, no somatic variants of the gene were found.

“These results suggest that second hits contribute to lesion persistency, whereas environmental factors leading to decreased expression of the wild-type allele result in the formation of less severe/transient DD lesions,” the researchers wrote.