Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

HNRNPK : Au-Kline Syndrome; AUKS

HGNC:5044 | OrphaNet: 453499 | OMIM:616580
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
6.0
6
Au PY et al. 2015 Oct (PMID:26173930); Lange L et al. 2016 Sep (PMID:26954065);
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families LOD Score Examples 3 5 0-7 7
2 4
1.5 3
1 1.5
   
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6 12
Total Genetic Evidence Points (Maximum 12) 6
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2 0.5 0.5
Fan X et al. 2015 Dec 7 (PMID:26638989);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4
Cell culture model system 1 0 - 2
Rescue in animal model 2 0 - 4
Rescue in engineered equivalent 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 0.5

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 6 0.5 6.5 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
CALCULATED CLASSIFICATION (DATE)
MODERATE
EXPERT CURATION (DATE)
MODERATE
11/15/2016
Evidence is rapidly emerging supporting the association between HNRNPK and Au-Kline syndrome. Gallardo et al. published a paper in 2015 describing an Hnrnpk +/- haploinsufficient mouse, which they developed to study its role in tumorigenesis. Personal communication with the senior author of that paper, Sean Post, in August 2016, revealed that the haploinsufficient mice appeared to have "significant reduction in overall size and had numerous structural/bone abnormalities," remniscient of the human phenotype, though he clarified that his group is not able to formally assess them for these types of phenotypes. Additionally, we are aware of at least one additional unpublished case - this evidence is not being formally considered, as it is not part of the public domain.