Functional Characterization of Variants in <i>LARP7</i>: Report of Three New Individuals With Alazami Syndrome and a Literature Review
Bibliographic record
Abstract
Introduction: Biallelic pathogenic variants in LARP7 result in Alazami syndrome, which is characterized by global developmental delay, cognitive dysfunction, and dysmorphic features. Cardiac and skeletal phenotypes are reported in about 30% of individuals. We report three new individuals with Alazami syndrome and functional characterization of LARP7 variants in this study. Materials and Methods: We reviewed electronic patient charts. We applied the American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification algorithms. We performed a 3D protein modeling tool for in silico prediction and functional characterization of LARP7 variants using qPCR gene expression experiments. We reviewed the medical literature for Alazami syndrome and LARP7 . Results: We report three individuals from two unrelated families with characteristic phenotypes suggestive of Alazami syndrome. We identified a homozygous novel missense LARP7 likely pathogenic variant (p.Asp54Val) in Family 1 and a homozygous novel pathogenic LARP7 variant (p.Lys219Glu∗) in Family 2 using clinical exome sequencing. 3D protein modeling showed large structural changes for both variants compared to wildtype. The functional characterization showed a statistically significant difference in LARP7 expression between affected individuals and wildtype control. We report phenotypic variability within the same family that the cardiac phenotype was only present in Family 1, Case 2. There were < 60 individuals with Alazami syndrome reported to date. Conclusion: We report three new individuals with Alazami syndrome and two novel variants in LARP7 . We report the first missense LARP7 variant associated with Alazami syndrome. We report the protein 3D structure of LARP7 variants. We show a relationship between the p.Asp54Val LARP7 variant and LARP7 expression levels. We think that this could be due to abnormal RNA binding of LARP7 as per the 3D protein modeling prediction tool.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".