Molecular diagnosis of rare inherited palmoplantar keratoderma (PPK) is still challenging. We investigated at the clinical and genetic level a consanguineous Tunisian family presenting an autosomal dominant atypical form of transgrediens and progrediens PPK to better characterize this ultrarare disease and to identify its molecular etiology. Whole-exome sequencing (WES), filtering strategies, and bioinformatics analysis have been achieved. Clinical investigation and follow up over 13 years of this Tunisian family with three siblings formerly diagnosed as an autosomal recessive form of Mal de Melela-like conducted us to reconsider its initial phenotype. Indeed, the three patients presented clinical features that overlap both Mal de Meleda and progressive symmetric erythrokeratoderma (PSEK). The mode of inheritance was also reconsidered, since the mother, initially classified as unaffected, exhibited a similar expression of the disease. WES analysis showed the absence of potentially functional rare variants in known PPKs or PSEK-related genes. Results revealed a novel heterozygous nonsynonymous variant in cadherin-12 gene (CDH12, NM_004061, c.1655C > A, p.Thr552Asn) in all affected family members. This variant is absent in dbSNP and in 50 in-house control exomes. In addition, in silico analysis of the mutated 3D domain structure predicted that this variant would result in cadherin-12 protein destabilization and thermal instability. Functional annotation and biological network construction data provide further supporting evidence for the potential role of CDH12 in the maintenance of skin integrity. Taken together, these results suggest that CDH12 gene is a potential candidate gene for an atypical presentation of an autosomal dominant form of transgrediens and progrediens PPK.

中文翻译：

---

在突尼斯家庭中，对常绿占优势的transgrediens和progrediens掌plant角化病的CDH12潜在候选基因变异的鉴定。

罕见的遗传性掌plant角化病（PPK）的分子诊断仍然具有挑战性。我们在临床和遗传水平上调查了近亲突尼斯家族，他们呈现常染色体显性非典型形式的transgrediens和progrediens PPK，以更好地表征这种罕见病并鉴定其分子病因。已实现全外显子测序（WES），过滤策略和生物信息学分析。对这个突尼斯家庭进行了13年的临床调查和随访，其中有3位兄弟姐妹先前被诊断为类似Mal de Melela的常染色体隐性遗传，这使我们重新考虑了其最初的表型。实际上，这三名患者的临床特征均与Mal de Meleda和进行性对称性红皮角化病（PSEK）重叠。还重新考虑了继承方式，因为最初被归类为未受影响的母亲表现出了类似的疾病表达。WES分析表明，已知PPK或PSEK相关基因中没有潜在功能的稀有变异。结果显示，在所有受影响的家庭成员中，钙粘着蛋白12基因（CDH12，NM_004061，c.1655C> A，p.Thr552Asn）均出现了一个新的杂合非同义变体。dbSNP和50个内部对照外显子组中没有此变体。另外，对突变的3D域结构的计算机分析预测该变体将导致cadherin-12蛋白不稳定和热不稳定。功能注释和生物网络构建数据为CDH12在维持皮肤完整性中的潜在作用提供了进一步的支持证据。在一起