Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".