■达里耶病(DD)是一种罕见的遗传性皮肤病,由ATP2A2基因的杂合变体引起。临床表现包括复发性角化性丘疹和斑块,主要发生在脂溢性区域。尽管一些病变因环境因素而出现蜡化,其他人则很严重,对治疗的反应较差。
■研究DD中皮肤病变持续存在的分子机制。
■在这种情况下,DNA是从未受影响的皮肤中提取的,短暂性和持续性皮损,和9例DD患者的血液。使用受影响的皮肤和血液的配对全外显子组测序或通过受影响的皮肤的ATP2A2的深度测序来使用遗传分析。染色体微阵列分析用于揭示拷贝数变异和杂合性丢失。通过Sanger测序或限制性片段长度多态性验证所有变体。
■对来自持久,DD患者的一过性病变和未受影响的皮肤。
■DD持续性和一过性皮肤病变的种系和体细胞基因组特征。
■在9例DD患者中,在ATP2A2基因中都有杂合致病种系变异,六是女性。参与者年龄在40至69岁之间。所有11个持续性皮肤病变均与ATP2A2基因中的第二次感染体细胞变异相关。通过结合注释依赖性缺失(CADD)评分或影响剪接,将体细胞变体分类为高度有害的,其中3例以前曾在DD和Hopf疣状肢端角化病患者中描述过。在短暂性病变(n=2)或正常皮肤(n=2)中未发现ATP2A2基因中的第二次攻击变体。
■在这项研究中,持续性DD病变与ATP2A2基因中存在二次感染体细胞变异相关.这些二次攻击变体的鉴定提供了对导致持续性DD病变的持久性的潜在机制的宝贵见解。
UNASSIGNED: Darier disease (DD) is a rare genetic skin disorder caused by heterozygous variants in the ATP2A2 gene. Clinical manifestations include recurrent hyperkeratotic papules and plaques that occur mainly in seborrheic areas. Although some of the lesions wax and wane in response to environmental factors, others are severe and respond poorly to therapy.
UNASSIGNED: To investigate the molecular mechanism underlying the persistency of skin lesions in DD.
UNASSIGNED: In this case series, DNA was extracted from unaffected skin, transient and persistent lesional skin, and blood from 9 patients with DD. Genetic analysis was used using paired-whole exome sequencing of affected skin and blood or by deep sequencing of ATP2A2 of affected skin. Chromosomal microarray analysis was used to reveal copy number variants and loss of heterozygosity. All variants were validated by Sanger sequencing or restriction fragment length polymorphism.
UNASSIGNED: Paired whole-exome sequencing and deep sequencing of ATP2A2 gene from blood and skin samples isolated from persistent, transient lesions and unaffected skin in patients with DD.
UNASSIGNED: Germline and somatic genomic characteristics of persistent and transient cutaneous lesions in DD.
UNASSIGNED: Of 9 patients with DD, all had heterozygous pathogenic germline variants in the ATP2A2 gene, 6 were female. Participant age ranged from 40 to 69 years on enrollment. All 11 persistent skin lesions were associated with second-hit somatic variants in the ATP2A2 gene. The somatic variants were classified as highly deleterious via combined annotation-dependent depletion (CADD) scores or affect splicing, and 3 of them had been previously described in patients with DD and acrokeratosis verruciformis of Hopf. Second-hit variants in the ATP2A2 gene were not identified in the transient lesions (n = 2) or the normal skin (n = 2).
UNASSIGNED: In this study, persistent DD lesions were associated with the presence of second-hit somatic variants in the ATP2A2 gene. Identification of these second-hit variants offers valuable insight into the underlying mechanisms that contribute to the lasting nature of persistent DD lesions.