<i>TMEM230</i> is not a gene for Parkinson’s disease
Bibliographic record
Abstract
Deng et al. report the discovery of TMEM230 c.422G>T (p.Arg141Leu) mutation as a cause of late-onset, autosomal dominant Parkinson's disease (PD) 1 in the same pedigree in which we previously assigned DNAJC13 c.2564A>G (p.Asn855Ser) as pathogenic 2. The chromosome 20pter-p12 locus was discovered by short tandem-repeat (STR) genotyping and linkage analysis, with subsequent exome sequencing in four affected (II-4, III-1, III-20 and III-26) and one unaffected family member.Deng et al. state the rationale for their re-analysis was the inconsistency of genotype-phenotype correlations for DNAJC13 c.2564A>G (p.Asn855Ser), this mutation being absent in three affected family members (II-1, III-1 and III-23).However, two of these suffer atypical parkinsonism; II-1 had clinical and pathologically-proven progressive supranuclear palsy, not Lewy body PD, whereas his son developed symptoms more than two decades earlier than the mean age at onset in the family.Based on haplotype and Sanger sequence analysis the authors' claim TMEM230 c.422G>T fully co-segregates with disease.Further discussion of these authors' claims is necessary.Our prior exome analysis of III-15 identified a DNAJC13 c.2564A>G (p.Asn855Ser) mutation but not TMEM230 c.422G>T (p.Arg141Leu) (Figure 1a).The exons of both genes had >30x sequence coverage and nucleotide sequences at both sites were confirmed by Sanger sequencing.In addition, our chromosome 20 STR marker genotyping, while consistent with parental/sibling haplotypes and Mendelian inheritance (Figure 1a) shows the genotyping presented by Deng et al. is erroneous for two individuals; III-14 at age 75 years is an unaffected carrier of TMEM230 c.422G>T (p.Arg141Leu) whereas III-15 is wild-type (Figure 1a, compare with Supplementary Fig. 1
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
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".