Division of Dermatology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.
Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
Clin Exp Dermatol. 2021 Jul;46(5):867-873. doi: 10.1111/ced.14569. Epub 2021 Mar 17.
Pachyonychia congenita (PC) refers to a group of autosomal dominant disorders caused by mutations in five keratin genes (KRT16,KRT6A,KRT17,KRT6B or KRT6C). Current disease classification is based on the gene harbouring disease-causing variants.
We harnessed the International Pachyonychia Congenita Research Registry (IPCRR) containing both clinical and molecular data on patients with PC worldwide, to identify genetic variants predicting disease severity.
We ascertained 815 individuals harbouring keratin mutations registered in the IPCRR. We looked for statistically significant associations between genetic variants and clinical manifestations in a subgroup of patients carrying mutations found in at least 10% of the cohort. Data were analysed using χ and Kruskal-Wallis tests.
We identified five mutations occurring in at least 10% of the patients registered in the IPCRR. The KRT16 p.L132P mutation was significantly associated with younger age of onset, presence of palmar keratoderma oral leucokeratosis and a higher number of involved nails. By contrast, the KRT16 p.N125S and p.R127C mutations resulted in a milder phenotype featuring a decreased number of involved nails and older age of onset. Patients carrying the p.N125S mutation were less likely to develop palmar keratoderma while p.R127C was associated with an older age of palmoplantar keratoderma onset. Moreover, the KRT17 p.L99P mutation resulted in an increased number of involved fingernails and patients demonstrating 20-nail dystrophy, while the opposite findings were observed with KRT17 p.N92S mutation.
We have identified novel and clinically useful genetic predictive variants in the largest cohort of patients with PC described to date.
先天性厚甲症（PC）是一组常染色体显性遗传疾病，由五个角蛋白基因（KRT16、KRT6A、KRT17、KRT6B 或 KRT6C）的突变引起。目前的疾病分类基于携带致病变异的基因。
我们利用包含全球 PC 患者临床和分子数据的国际先天性厚甲症研究注册处（IPCRR），确定预测疾病严重程度的遗传变异。
我们确定了在 IPCRR 中注册的携带角蛋白突变的 815 个人。我们在携带至少 10%队列中发现的突变的患者亚组中，寻找遗传变异与临床表现之间的统计学显著关联。数据使用 χ 和 Kruskal-Wallis 检验进行分析。
我们确定了在 IPCRR 中注册的至少 10%患者中发生的五个突变。KRT16 p.L132P 突变与发病年龄较小、手掌角化过度、口腔白角化病和受累指甲数量较多显著相关。相比之下，KRT16 p.N125S 和 p.R127C 突变导致受累指甲数量减少和发病年龄较大的轻度表型。携带 p.N125S 突变的患者发生手掌角化过度的可能性较小，而 p.R127C 与掌跖角化过度发病年龄较大相关。此外，KRT17 p.L99P 突变导致受累指甲数量增加，患者表现为 20 指甲营养不良，而 KRT17 p.N92S 突变则相反。
我们在迄今为止描述的最大 PC 患者队列中确定了新的、具有临床意义的遗传预测变异。
