<b><i>CYP24A1</i></b> and <b><i>SLC34A1</i></b> Pathogenic Variants Are Uncommon in a Canadian Cohort of Children with Hypercalcemia or Hypercalciuria
Bibliographic record
Abstract
<b><i>Objectives:</i></b> Biallelic pathogenic variants in <i>CYPA24A1</i> and <i>SLC34A1</i> are causes of idiopathic infantile hypercalcemia. Pathogenic variants in both may also give rise to hypercalciuria with nephrocalcinosis or nephrolithiasis without previous hypercalcemia (renal group). Our objective was to examine the frequency of <i>CYP24A1</i> or <i>SLC34A1</i> variants in children with early hypercalcemia or late-onset hypercalciuria. <b><i>Method:</i></b> Forty-one children from 7 centers across Canada were recruited. Local investigations were undertaken. The serum was evaluated by liquid chromatography tandem-mass spectrometry for the ratio of 25-hydroxyvitamin D<sub>3</sub> to 24,25-dihydroxyvitamin D<sub>3</sub>, (25-OH-D<sub>3</sub>:24,25-(OH)<sub>2</sub>D<sub>3</sub>), an elevation pathognomonic for the loss of function of the <i>CYP24A1</i> enzyme. Mutational analyses were undertaken. Family cascade screening was performed if pathogenic variants were detected in probands. <b><i>Results:</i></b> Twenty-nine children had early-onset hypercalcemia; none had elevated 25-OH-D<sub>3</sub>:24,25-(OH)<sub>2</sub>D<sub>3</sub> or variants. Interestingly, 2 of 12 in the renal group had elevated 25-OH-D<sub>3</sub>:24,25-(OH)<sub>2</sub>D<sub>3</sub> and presented as preadolescents. In case 1, cascade testing revealed a sibling and parent with asymptomatic pathogenic variants in <i>CYP24A1.</i> Four <i>CYP24A1</i> pathogenic variants were identified in these 2 probands: 3 have been described in European populations, and 1 is a rare variant in exon 7 (c931delC) that is likely pathogenic. No <i>SLC34A1</i> pathogenic variants were detected. <b><i>Conclusion:</i></b> In Canada, pathogenic variants in <i>CYP24A1</i> appear to manifest with late-onset hypercalciuria and its sequelae. The 25-OH-D<sub>3</sub>:24,25-(OH)<sub>2</sub>D<sub>3</sub> ratio is an excellent tool for screening for biallelic pathogenic variants in <i>CYP24A1</i>. We confirm that cascade testing is important for these variants.
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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 | 0.016 | 0.016 |
| Meta-epidemiology (narrow) | 0.004 | 0.003 |
| Meta-epidemiology (broad) | 0.007 | 0.001 |
| Bibliometrics | 0.009 | 0.018 |
| Science and technology studies | 0.002 | 0.004 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.004 | 0.004 |
| Research integrity | 0.003 | 0.007 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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; both teacher heads agree on what is shown here.
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".