OR23-02 Genotype-Phenotype Correlation In Calcium Sensing Receptor (Casr) Gene Gain-Of-Function Mutations: A Case Series And Report Of 2 Novel Mutations
Bibliographic record
Abstract
Abstract Disclosure: D.S. Ali: None. F. Marini: None. F. Alsarraf: None. H.H. Alalwani: None. A. Alamri: None. A.A. Khan: Advisory Board Member; Self; Amgen Inc, Takeda. Grant Recipient; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Takeda, Ultragenyx, Radius Health, Inc. M. Brandi: Consulting Fee; Self; Alexion Pharmaceuticals, Inc. Speaker; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Eli Lilly & Company. Background: Autosomal dominant hypocalcemia (ADH1) is a genetic disorder characterized by low serum calcium and low or inappropriately normal parathyroid hormone levels. It is caused by a heterozygous activating mutation of the calcium-sensing receptor (CaSR) gene. ADH1 has been linked to 113 unique germline mutations, of which 96% are missense mutations. There is a lack of clear genotype-phenotype correlation in the reported literature. Methods: We described a case series of six unrelated ADH1 probands, each with a gain-of-function CaSR mutation, and two children of one of these cases, comparing clinical, biochemical, and complication profiles and matching our identified mutations to those previously reported in the literature. Results: Of our cases 75% are familial and 25% are secondary to de novo mutation. Our 6 unrelated ADH1 probands showed distinct clinical presentations, while 3 cases within the same pedigree shared similar presentation and clinical characteristics including presentation in infancy, hypocalcemic seizures (2/3; 66.7%), hypomagnesemia, hyperphosphatemia, and hypercalciuria. The biochemical profile differed among the 6 cases in the degree of hypocalcemia, associated hypercalciuria, hypomagnesemia, and/or hypokalemia. Response to therapy also differed. When comparing our cases to previously published cases, we noted that mutations in the 5th transmembrane domain of the CaSR (TM5) carry a more severe form of the disease and may be associated with a higher rate of hypocalcemic seizures, basal ganglia calcifications as well as nephrocalcinosis, nephrolithiasis and renal insufficiency compared to mutations in the extracellular regions. Hypomagnesemia was present in 100% of the cases harboring mutations in TM5. We also describe two novel activating mutations of the CaSR gene; c.2468T>A, p.lle823Asn and c.1756G>A, p.Glu586Lys. Both of these were not reported either on the most common databases of human mutations or in the literature. In silico analysis of p.lle823Asn by PolyPhen-2 predicted the Ile to Asn substitution at position 823 as “probably damaging”, while the p.Glu586Lys substitution was suggested to have a “benign” nature. Our patient with the former mutation had a history of seizure and nephrolithiasis, while our patient with the latter mutation is mildly symptomatic, presented in her 40s, and is on low doses of active vitamin D and calcium supplements. Conclusion: As a result of these genetic and clinical comparisons, we propose that a genotype-phenotype correlation may exist because our cases showed similar presentation, characteristics, and severity, with respect to published cases with the same or similar mutations. We also contended that the severity of the presentation is highly influenced by the specific CaSR variant. These findings, however, require further evaluation and assessment with a systematic review. Presentation: Saturday, June 17, 2023
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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 | 0.001 | 0.004 |
| Meta-epidemiology (narrow) | 0.003 | 0.002 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.004 | 0.002 |
| Science and technology studies | 0.002 | 0.002 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.005 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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; 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".