LRP4 mutations in bilateral renal agenesis with severe limb deficiencies
Bibliographic record
Abstract
Introduction : Severe limb deficiencies have been reported in association with bilateral renal agenesis in several syndromes. Recently, truncating mutations in LRP4 have been associated with a lethal autosomal recessive form of Cenani-Lenz syndrome (CLS). The objectives of our study was to delineate the phenotype of the third fetus, and through a search of syndromes, identify a group of disorders with overlapping phenotypes that may be allelic with CLS or due to mutations in the same pathway. Results : A male fetus at 22 weeks’ gestation was found to have bilateral renal agenesis by ultrasound. The pregnancy was interrupted and autopsy and skeletal survey revealed shortening of forearms and legs below the knees, radioulnar synostosis, foreshortened triangular shaped tibia and fibula, and oligosyndactyly with disorganized metacarpals, metatarsals and phalanges. Bilateral renal agenesis, absent ureters and small bladder were confirmed. Additional features included downslanting palpebral fissures, high-arched palate, small mouth, low-set and posteriorly rotated ears, nuchal oedema, pulmonary hypoplasia, hypospadias and absent olfactory nerves. An autosomal recessive disorder was suspected, given a prior obstetric history of termination at 18 weeks for unilateral limb anomalies and cleft lip. Based on the aforementioned renal and limb anomalies, the lethal form of CLS was considered. Sequencing of LRP4 identified a paternally inherited variant (c.919+3G del) and a maternally inherited variant (c.4808T>A ;p.Ile1603Val). Both variants were rare in the general population and bioinformatically predicted to be damaging. We compared the phenotype with the two previously reported fetuses as well as with syndromes and disorders that may present prenatally with genitourinary anomalies plus acromesomelia of upper and lower limbs. We found significant overlap with a subset of cases of acro-renal-uterine-mandibular syndrome presenting with high-arched palate plus or minus micrognathia and microglossia, severe limb anomalies affecting the middle and distal segments, oligosyndactyly, renal agenesis, uterine anomalies and absence of olfactory nerves. Conclusion : Based on the clinical features seen in three lethal cases of CLS, we propose that acro-renal-uterine-mandibular syndrome may be allelic with CLS or due to mutations in the molecular pathway involving LRP4.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".