Gene Validity Curation

INS - permanent neonatal diabetes mellitus

Gene: INS (HGNC:6081)
Classification - 05/13/2020
Disease: permanent neonatal diabetes mellitus (MONDO_0011643)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Monogenic Diabetes EP
Evidence Summary: INS and autosomal recessive monogenic diabetes INS was first reported in relation to autosomal recessive monogenic diabetes in 2010. The phenotype is usually permanent neonatal diabetes with intrauterine growth retardation requiring insulin treatment, but some individuals who are homozygous or compound heterozygous for INS regulatory variants were reported to have transient neonatal diabetes (diagnosed in early infancy but diabetes was in clinical remission at the time of publication after limited follow-up period) or diabetes diagnosed outside the neonatal period rather than permanent neonatal diabetes (Garin et al., PMID:20133622). At least 11 unique variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level and experimental data: 16 points. Variants in this gene have been reported in at least 12 probands in 6 publications (PMIDS: 31441606, 26101329, 27487489, 25755231, 23245869, 20133622). The mechanism for disease is expected to be loss of function. This gene-disease association is supported by expression studies, animal models, and cell culture models. In summary, INS is definitively associated with autosomal recessive permanent neonatal diabetes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Per criteria outlined by the ClinGen Lumping and Splitting working group, we found differences in molecular mechanisms, inheritance patterns, and phenotypic variability underlying the disease entities associated with INS. Therefore, we have split curations for these disease entities. The present curation refers to the entity of autosomal recessive permanent neonatal diabetes (MIM: 606176) with some rare transient neonatal of older onset cases. Other entities being curated separately include (1) autosomal dominant monogenic diabetes, which comprises OMIM entries autosomal dominant neonatal diabetes (MIM: 606176) and maturity-onset diabetes of the young 10 (MODY10; MIM:613370) and (2) hyperproinsulinemia (MIM: 616214). Type 1 diabetes (polygenic; MIM: 125852) will not be curated at this time since the contribution of INS is in the form of common variants with a small effect.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
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 3
5
12
Garin I et al. 2010 Feb 16 (PMID:20133622); Di Benedetto M et al. 2013 Feb (PMID:23245869);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 9
7.5
Al-Khawaga S et al. 2019 Oct (PMID:31441606); Garin I et al. 2010 Feb 16 (PMID:20133622); Courtney R et al. 2016 Sep 1 (PMID:27487489); Demirbilek H et al. 2015 Jun (PMID:25755231); Carmody D et al. 2015 Sep (PMID:26101329);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Fagerberg L et al. 2014 Feb (PMID:24309898); GTEx Consortium et al. 2013 Jun (PMID:23715323);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 3
Ma S et al. 2018 Dec 11 (PMID:30503261);
Cell culture model 1 0 - 2 1 1
Ma S et al. 2018 Dec 11 (PMID:30503261);
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4

 


 

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 12 4 16 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
06/09/2020
EXPERT CURATION (DATE)
Definitive
05/13/2020
EVIDENCE SUMMARY
INS and autosomal recessive monogenic diabetes INS was first reported in relation to autosomal recessive monogenic diabetes in 2010. The phenotype is usually permanent neonatal diabetes with intrauterine growth retardation requiring insulin treatment, but some individuals who are homozygous or compound heterozygous for INS regulatory variants were reported to have transient neonatal diabetes (diagnosed in early infancy but diabetes was in clinical remission at the time of publication after limited follow-up period) or diabetes diagnosed outside the neonatal period rather than permanent neonatal diabetes (Garin et al., PMID:20133622). At least 11 unique variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level and experimental data: 16 points. Variants in this gene have been reported in at least 12 probands in 6 publications (PMIDS: 31441606, 26101329, 27487489, 25755231, 23245869, 20133622). The mechanism for disease is expected to be loss of function. This gene-disease association is supported by expression studies, animal models, and cell culture models. In summary, INS is definitively associated with autosomal recessive permanent neonatal diabetes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Per criteria outlined by the ClinGen Lumping and Splitting working group, we found differences in molecular mechanisms, inheritance patterns, and phenotypic variability underlying the disease entities associated with INS. Therefore, we have split curations for these disease entities. The present curation refers to the entity of autosomal recessive permanent neonatal diabetes (MIM: 606176) with some rare transient neonatal of older onset cases. Other entities being curated separately include (1) autosomal dominant monogenic diabetes, which comprises OMIM entries autosomal dominant neonatal diabetes (MIM: 606176) and maturity-onset diabetes of the young 10 (MODY10; MIM:613370) and (2) hyperproinsulinemia (MIM: 616214). Type 1 diabetes (polygenic; MIM: 125852) will not be curated at this time since the contribution of INS is in the form of common variants with a small effect.