Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Department of Dermatology, Immunodermatology and Venereology, Medical University of Warsaw, Warsaw, 02-008, Poland.
Orphanet J Rare Dis. 2024 Nov 5;19(1):413. doi: 10.1186/s13023-024-03395-4.
The Mendelian Disorders of Cornification (MeDOC) comprise a large number of disorders that present with either localised (palmoplantar keratoderma, PPK) or generalised (ichthyoses) signs. The MeDOC are highly heterogenic in terms of genetics and phenotype. Consequently, diagnostic process is challenging and before implementation of the next generation sequencing, was mostly symptomatic, not causal, which limited research on those diseases. The aim of the study was to genetically characterise a cohort of 265 Polish patients with MeDOC and to get insight into the skin lesions using transcriptome and lipid profile analyses.
We detected causal variants in 85% (226/265) patients. In addition to the primary gene defect, a pathogenic variant in another gene involved in MeDOC pathology was identified in 23 cases. We found 150 distinct variants in 33 genes, including 32 novel and 16 recurrent (present in > 5 alleles). In 43 alleles large rearrangements were detected, including deletions in the STS, SPINK5, CERS3 and recurrent duplication of exons 10-14 in TGM1. The RNA analysis using samples collected from 18 MeDOC patients and 22 controls identified 1377 differentially expressed genes - DEG. The gene ontology analysis revealed that 114 biological processes were upregulated in the MeDOC group, including i.e. epithelial cell differentiation, lipid metabolic process; homeostasis; regulation of water loss via skin; peptide cross-linking. The DEG between TGM1 and ALOX12B patients, showed that RNA profile is highly similar, though fatty acid profile in epidermal scrapings of those patients showed differences e.g. for the very long chain fatty acids (VLCFAs; FAs ≥ C20), the very long-chain monounsaturated fatty acids (VLC-MUFAs, FAs ≥ C20:1) and the n6 polyunsaturated fatty acids (n6 PUFAs).
Our results show that NGS-based analysis is an effective MeDOC diagnostic tool. The Polish MeDOC patients are heterogenic, however recurrent variants are present. The novel variants and high number of TGM1 and SPINK5 copy number variations give further insight into molecular pathology of MeDOC. We show that secondary variants in MeDOC-related genes are present in a significant group of patients, which should be further investigated in the context of phenotype modifiers. Finally, we provide novel RNA and lipid data that characterise molecularly MeDOC epidermis.
角化不良性先天性鱼鳞病（MeDOC）包括大量以局部（掌跖角化过度症，PPK）或全身（鱼鳞癣）表现的疾病。在遗传和表型方面，MeDOC 高度异质性。因此，诊断过程具有挑战性，在下一代测序实施之前，主要是症状性的，而非因果性的，这限制了对这些疾病的研究。本研究的目的是对 265 名波兰 MeDOC 患者进行基因特征分析，并通过转录组和脂质谱分析深入了解皮肤损伤。
我们在 85%（226/265）的患者中检测到致病变异。除了主要的基因缺陷外，在 23 例患者中还发现了另一个涉及 MeDOC 病理的基因的致病性变异。我们在 33 个基因中发现了 150 个不同的变异，包括 32 个新变异和 16 个重复变异（存在于> 5 个等位基因中）。在 43 个等位基因中检测到大片段重排，包括 STS、SPINK5、CERS3 缺失和 TGM1 外显子 10-14 的重复。使用 18 名 MeDOC 患者和 22 名对照的样本进行 RNA 分析，确定了 1377 个差异表达基因（DEG）。基因本体论分析表明，MeDOC 组中有 114 个生物学过程上调，包括上皮细胞分化、脂质代谢过程、稳态、通过皮肤失水调节、肽交联。TGM1 和 ALOX12B 患者之间的 DEG 表明，RNA 谱非常相似，尽管这些患者的表皮刮片中的脂肪酸谱存在差异，例如超长链脂肪酸（VLCFAs；FA≥C20）、超长链单不饱和脂肪酸（VLC-MUFAs，FA≥C20:1）和 n6 多不饱和脂肪酸（n6 PUFAs）。
我们的结果表明，基于 NGS 的分析是一种有效的 MeDOC 诊断工具。波兰 MeDOC 患者是异质性的，但存在反复出现的变异。新的变异和大量 TGM1 和 SPINK5 拷贝数变异进一步阐明了 MeDOC 的分子病理学。我们表明，MeDOC 相关基因中的二级变异存在于相当一部分患者中，这需要进一步从表型修饰剂的角度进行研究。最后，我们提供了新的 RNA 和脂质数据，这些数据可从分子水平上对 MeDOC 表皮进行特征描述。
