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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.

Sensenbrenner syndrome, also known as cranioectodermal dysplasia, is a rare multiple anomaly syndrome with distinctive craniofacial appearance, skeletal, ectodermal, connective tissue, renal, and liver anomalies. Dramatic advances with next-generation sequencing have expanded its phenotypic variability and molecular heterogeneity. We review 39 patients including two new patients, one with compound heterozygous novel mutations in WDR35 and a previously unreported multisutural craniosynostosis that may be a part of Sensenbrenner syndrome. In 14 of 25 (56.0%) patients pathogenic mutations have been identified in 4 different genes that regulate (intraflagellar) cilia transport. We compared Sensenbrenner syndrome to asphyxiating thoracic dystrophy-Jeune syndrome (ATD-JS) and other ciliopathies. Our analyses showed that the high anterior hairline, forehead bossing and dolichocephaly (accompanied by sagittal craniosynostosis in more than half of the patients) occur in almost all patients with Sensenbrenner syndrome. Metaphyseal dysplasia with narrow thorax, proximal limb shortness, and short fingers are typical of Sensenbrenner syndrome and ATD-JS. Respiratory complications have been reported in both syndromes, usually less severe with Sensenbrenner syndrome. Proposed diagnostic criteria for Sensenbrenner syndrome include the distinctive craniofacial appearance, ubiquitous brachydactyly and ectodermal anomalies, and sagittal craniosynostosis. Mild heart defects have been noted, but there have been no atrioventricular canal or heterotaxy defects that are common in Ellis-Van Creveld syndrome. We anticipate that the steady identification of molecularly defined patients may allow correlation of phenotype and genotype. Additional natural history data will improve genetic counseling and current guidelines., (© 2013 Wiley Periodicals, Inc.)

A subset of ciliopathies, including Sensenbrenner, Jeune, and short-rib polydactyly syndromes are characterized by skeletal anomalies accompanied by multiorgan defects such as chronic renal failure and retinitis pigmentosa. Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome. In a Dutch family with the clinically overlapping Jeune syndrome, a homozygous missense mutation in the same gene was found. Both families displayed a nephronophthisis-like nephropathy. Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis. WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport. We show that IFT144 is absent from the cilia of fibroblasts from one of the Sensenbrenner patients and that ciliary abundance and morphology is perturbed, demonstrating the ciliary pathogenesis. Our results suggest that isolated nephronophthisis, Jeune, and Sensenbrenner syndromes are clinically overlapping disorders that can result from a similar molecular cause., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Sensenbrenner syndrome is a heterogeneous ciliopathy that is characterised by skeletal and ectodermal anomalies, accompanied by chronic renal failure, heart defects, liver fibrosis and other features., Objective: To identify an additional causative gene in Sensenbrenner syndrome., Methods: Single nucleotide polymorphism array analysis and standard sequencing techniques were applied to identify the causative gene. The effect of the identified mutation on protein translation was determined by western blot analysis. Antibodies against intraflagellar transport (IFT) proteins were used in ciliated fibroblast cell lines to investigate the molecular consequences of the mutation on ciliary transport., Results: Homozygosity mapping and positional candidate gene sequence analysis were performed in two siblings with Sensenbrenner syndrome of a consanguineous Moroccan family. In both siblings, a homozygous mutation in the initiation codon of C14ORF179 was identified. C14ORF179 encodes IFT43, a subunit of the IFT complex A (IFT-A) machinery of primary cilia. Western blots showed that the mutation disturbs translation of IFT43, inducing the initiation of translation of a shorter protein product from a downstream ATG. The IFT-A protein complex is implicated in retrograde ciliary transport along axonemal microtubules. It was shown that in fibroblasts of one of the siblings affected by Sensenbrenner syndrome, disruption of IFT43 disturbs this transport from the ciliary tip to its base. As anterograde transport in the opposite direction apparently remains functional, the IFT complex B proteins accumulate in the ciliary tip. Interestingly, similar results were obtained using fibroblasts from a patient with Sensenbrenner syndrome with mutations in WDR35/IFT121, encoding another IFT-A subunit., Conclusions: The results indicate that Sensenbrenner syndrome is caused by disrupted IFT-A-mediated retrograde ciliary transport.

Sensenbrenner syndrome/cranioectodermal dysplasia (CED) is an autosomal-recessive disease that is characterized by craniosynostosis and ectodermal and skeletal abnormalities. We sequenced the exomes of two unrelated CED patients and identified compound heterozygous mutations in WDR35 as the cause of the disease in each of the two patients independently, showing that it is possible to find the causative gene by sequencing the exome of a single sporadic patient. With RT-PCR, we demonstrate that a splice-site mutation in exon 2 of WDR35 alters splicing of RNA on the affected allele, introducing a premature stop codon. WDR35 is homologous to TULP4 (from the Tubby superfamily) and has previously been characterized as an intraflagellar transport component, confirming that Sensenbrenner syndrome is a ciliary disorder., (2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)