Nurelegne Hasset T, Thompson Mone't B, de Andrade Kelvin C, Thompson Ashley S, McReynolds Lisa J, Niewisch Marena R, Savage Sharon A
Clinical Genetics Branch, Division of Cancer and Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Mol Genet Genomic Med. 2025 Jun;13(6):e70107. doi: 10.1002/mgg3.70107.
PARN encodes poly(A)-specific ribonuclease, a 3 exoribonuclease important in regulating RNA stability and maturation. Rare germline PARN variants have been reported in telomere biology disorders (TBDs) leading to its inclusion on gene panels for bone marrow failure syndromes and pulmonary diseases.
To understand the extent of germline PARN variation in human disease, we conducted a comprehensive literature review, curated the TBD-associated PARN variants using AutoGVP and in silico prediction tools (MetaSVM, REVEL, and/or CADD) and assessed their frequency in the gnomAD database.
Ninety-three unique PARN variants were identified in the literature as present in individuals or families affected by TBDs, but clinical features were not consistently reported. Forty-one variants (44.1%) were classified as pathogenic or likely pathogenic. These variants were spread across the entire gene with no obvious clustering. gnomAD data were notable for a paucity of common variants and metrics suggesting PARN variation would be tolerated.
The extent to which specific PARN variants can be associated with TBD etiology is limited due to incomplete literature, clinical data, lack of robust functional assays, and high frequency of rare variants.
PARN编码聚腺苷酸特异性核糖核酸酶，这是一种3'外切核糖核酸酶，在调节RNA稳定性和成熟过程中起重要作用。罕见的种系PARN变异已在端粒生物学障碍（TBD）中被报道，这导致其被纳入骨髓衰竭综合征和肺部疾病的基因检测板。
为了解人类疾病中种系PARN变异的程度，我们进行了全面的文献综述，使用自动基因组变异数据库（AutoGVP）和计算机预测工具（MetaSVM、REVEL和/或CADD）筛选与TBD相关的PARN变异，并评估它们在gnomAD数据库中的频率。
在文献中鉴定出93个独特的PARN变异存在于受TBD影响的个体或家庭中，但临床特征的报告并不一致。41个变异（44.1%）被分类为致病性或可能致病性。这些变异分布在整个基因中，没有明显的聚集现象。gnomAD数据显示常见变异很少，且各项指标表明PARN变异是可以耐受的。
由于文献不完整、临床数据缺乏、缺乏可靠的功能检测以及罕见变异的高频率，特定PARN变异与TBD病因学相关的程度有限。
