BACKGROUND Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes (IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra- and interfamilial clinical variability has been reported in CED, which is consistent with CED's genetic heterogeneity and is indicative of genetic background effects. RESULTS Two male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed distinctive clinical features of Sensenbrenner syndrome, such as dolichocephaly, shortening of long bones and early onset renal failure. Ectodermal anomalies also included thin hair, short and thin nails, and small teeth in both patients. Next generation sequencing (NGS) techniques were performed in order to determine the underlying genetic cause of the disorder using whole exome sequencing (WES) for patient 1 and a custom NGS-based panel for patient 2. Subsequent qPCR and duplex PCR analysis were conducted for both patients. Genetic analyses identified compound heterozygous variants in the IFT140 gene in both affected individuals. Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele. In addition, a novel missense variant, p.(Leu109Pro), and a previously described p.(Gly522Glu) variant were identified in the second allele in patients 1 and 2, respectively. Segregation analysis of the variants was consistent with the expected autosomal recessive disease inheritance pattern. Both patients had severe renal failure requiring kidney transplantation in early childhood. CONCLUSION The finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome. Our studies confirm that IFT140 changes in patients with CED are associated with early onset end-stage renal disease. Moreover, this report expands our knowledge of the clinical- and molecular genetics of Sensenbrenner syndrome and it highlights the importance of multidisciplinary approaches in the care of CED patients.

中文翻译：

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两个具有Sensenbrenner综合征和早期发作的终末期肾脏疾病的波兰家庭中的复合杂合IFT140变体。

背景技术Sensenbrenner综合征，也称为颅外胚层发育不良（CED），是一种罕见的常染色体隐性睫状软骨发育不良，其特征是多种临床特征，包括独特的颅面外观以及骨骼，外胚层，肝脏和肾脏异常。在这种情况下，进行性肾脏疾病可能危及生命。CED是遗传异质性疾病。目前，六个基因（IFT122，WDR35，IFT140，IFT43，IFT52和WDR19）中的任何一个变异都已与该综合征相关。所有这些基因编码鞭毛内运输（IFT）所必需的蛋白质，而纤毛内部运输是纤毛组装，维持和功能所必需的过程。据报道，CED的家庭内和家庭间临床差异性与CED'相符。遗传异质性，表明遗传背景效应。结果本研究包括来自两个不相关的波兰家庭的两名男性CED患者。临床评估显示，Sensenbrenner综合征具有鲜明的临床特征，例如头颅畸形，长骨缩短和早期肾功能衰竭。皮肤外胚层异常还包括两名患者的稀疏的头发，短而又薄的指甲和小牙齿。为了确定患者1的整体外显子组测序（WES）和患者2的定制NGS基检测组，进行了下一代测序（NGS）技术，以确定该疾病的潜在遗传原因。随后进行了qPCR和双链PCR分析两个病人。遗传分析确定了两个受影响个体的IFT140基因中的复合杂合变异体。两名患者在一个等位基因上均具有串联复制变体p.Tyr1152_Thr1394dup。另外，在患者1和2的第二等位基因中分别鉴定出新的错义变体p。（Leu109Pro）和先前描述的p。（Gly522Glu）变体。变异的分离分析与预期的常染色体隐性疾病遗传模式一致。两名患者均患有严重的肾衰竭，需要在儿童早期进行肾脏移植。结论在两名无关的CED患者中发现复合杂合IFT140突变，为IFT140基因突变与该综合征相关提供了进一步的证据。我们的研究证实，CED患者的IFT140变化与早期发作的终末期肾脏疾病有关。此外，