Autosomal Dominant Non-Syndromic Hearing Loss Maps to DFNA33 (13q34) and Co-Segregates with Splice Site Variants in ATP11A, A Phospholipid Flippase Gene
Bibliographic record
Abstract
Abstract Whole genome approaches are superior for identifying recessive genes, however discovery of dominant genes including deafness genes (DFNA) remains challenging. Herein we report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Targeted screening of DFNA genes based on audioprofiles was unsuccessful. Genome-wide SNP genotyping linked SNHL to DFNA33 (Lod = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL in 2009. WGS identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 Kb, excluding all but one variant. ATP11A (NC_000013.11: g.190616G > A) is a novel point mutation predicted to be a cryptic donor splice site. RNA studies in patient-derived tissues verified in silico predictions, revealing the retention of 153bp of intron in the 3’ UTR of several ATP11A isoforms. A second, unresolved family from Israel with a similar, variable form of SNHL and a novel duplication in exon 28 of ATP11A that occurs within the splice donor sequence (intron 28). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.006 | 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 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".