Biallelic loss-of-function variants of SLC12A9 cause lysosome dysfunction and a syndromic neurodevelopmental disorder
Bibliographic record
Abstract
Purpose: Pathogenic variants of FIG4 generate enlarged lysosomes and neurological and developmental disorders.To identify additional genes regulating lysosomal volume, we carried out a genome-wide activation screen to detect suppression of enlarged lysosomes in FIG4 -/-cells.Methods: The CRISPR-a gene activation screen utilized sgRNAs from the promoters of proteincoding genes.Fluorescence-activated cell sorting separated cells with correction of the enlarged lysosomes from uncorrected cells.Patient variants of SLC12A9 were identified by exome or genome sequencing and studied by segregation analysis and clinical characterization.Results: Overexpression of SLC12A9, a solute co-transporter, corrected lysosomal swelling in FIG4 -/-cells.SLC12A9 (NP_064631.2) colocalized with LAMP2 at the lysosome membrane.Biallelic variants of SLC12A9 were identified in 3 unrelated probands with neurodevelopmental disorders.Common features included intellectual disability, skeletal and brain structural abnormalities, congenital heart defects, and hypopigmented hair.Patient 1 was homozygous for nonsense variant p.(Arg615*), patient 2 was compound heterozygous for p.(Ser109Lysfs*20) and a large deletion, and proband 3 was compound heterozygous for p.(Glu290Glyfs*36) and p.(Asn552Lys).Fibroblasts from proband 1 contained enlarged lysosomes that were corrected by wild-type SLC12A9 cDNA.Patient variant p.(Asn552Lys) failed to correct the lysosomal defect.Conclusion: Impaired function of SLC12A9 results in enlarged lysosomes and a recessive disorder with a recognizable neurodevelopmental phenotype.
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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) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".