Gene Validity Curation

INS - monogenic diabetes

Gene: INS (HGNC:6081)
Classification - 05/13/2020
Disease: monogenic diabetes (MONDO_0015967)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Monogenic Diabetes EP
Evidence Summary: INS was first reported in relation to autosomal dominant monogenic diabetes in 2007 (Støy, et al., PMID: 17855560) and studies of large case series reported in 2008 indicated INS mutations as the second most common cause of permanent neonatal diabetes. While most reported cases are diagnosed with diabetes before 6 months of age, diabetes is less commonly diagnosed later in infancy or early childhood, as well as rarely in adolescence or early adulthood (PMID: 18162506, 18292540), sometimes referred to as MODY10 (MIM:613370). The mechanism for disease in the majority of cases is expected to be toxic gain of function, related to misfolding of the proinsulin molecule leading to ER stress and apoptosis (PMID: 9884331); consequently, these cases usually require and respond best to insulin treatment. Of note, a few studies have found such INS mutations in approximately 7% of patients who had been clinically diagnosed with type 1 diabetes in early childhood but were negative for pancreatic autoantibodies. A few INS variants appear to have distinct mechanisms affecting properties such as protein stability and/or binding to the insulin receptor. Patients with these variants appear more likely to be diagnosed with diabetes in adolescence or early adulthood and may respond to oral hypoglycemic agents (PMID: 18192540). Numerous variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of case-level and experimental data: 17.6 points. Variants in this gene have been reported in at least 11 probands in 7 publications (PMIDs: 17855560, 25721872, 816250, 20007936, 18192540, 19900242, 30182532, 28992123). Variants in this gene segregated with disease in 11 additional family members. A score of 11.6 was achieved for genetic data. This gene-disease association is supported by expression studies, animal models, and in vitro functional assays. In summary, INS is definitively associated with autosomal dominant monogenic 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 INS-related disease entities. Therefore, we have split curations for these disease entities. The present curation includes (1) autosomal dominant monogenic diabetes mellitus, which most often presents in infancy and is usually referred to as permanent neonatal diabetes (MIM: 606176), but may also occur in patients with antibody-negative type 1 diabetes in early childhood, or rarely in adolescence or young adulthood and may be referred to as maturity-onset diabetes of the young 10, (MODY10, MIM:613370). Other entities requiring separate curations include (2) Autosomal recessive diabetes mellitus (usually permanent neonatal; MIM: 606176) and (3) 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 2
4
4
Rubio-Cabezas O et al. 2009 Oct (PMID:19900242);
Proband with predicted or proven null variant 1.5 0-2 10 3 4.5 4.5
Dusatkova L et al. 2015 Apr (PMID:25721872); Xiao X et al. 2019 Jan (PMID:30182532);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 6
2.6
2.6
Edghill EL et al. 2008 Apr (PMID:18162506); Molven A et al. 2008 Apr (PMID:18192540); Yan J et al. 2017 Oct 1 (PMID:28992123); Meur G et al. 2010 Mar (PMID:20007936);
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   Summed LOD Family Count 0.5 0.5  
Candidate gene sequencing 2.71 2
Meur G et al. 2010 Mar (PMID:20007936); Xiao X et al. 2019 Jan (PMID:30182532);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 2.71    
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) 11.6
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
1
Non-patient cells 0.5 0 - 1 2 1
Wang J et al. 1999 Jan (PMID:9884331); Haneda M et al. 1985 Jun (PMID:3891469);
Models Non-human model organism 2 0 - 4 4 2 4 4
Wang J et al. 1999 Jan (PMID:9884331); Duvillié B et al. 1997 May 13 (PMID:9144203);
Cell culture model 1 0 - 2
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) 6

 


 

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 11.6 6 17.6 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 was first reported in relation to autosomal dominant monogenic diabetes in 2007 (Støy, et al., PMID: 17855560) and studies of large case series reported in 2008 indicated INS mutations as the second most common cause of permanent neonatal diabetes. While most reported cases are diagnosed with diabetes before 6 months of age, diabetes is less commonly diagnosed later in infancy or early childhood, as well as rarely in adolescence or early adulthood (PMID: 18162506, 18292540), sometimes referred to as MODY10 (MIM:613370). The mechanism for disease in the majority of cases is expected to be toxic gain of function, related to misfolding of the proinsulin molecule leading to ER stress and apoptosis (PMID: 9884331); consequently, these cases usually require and respond best to insulin treatment. Of note, a few studies have found such INS mutations in approximately 7% of patients who had been clinically diagnosed with type 1 diabetes in early childhood but were negative for pancreatic autoantibodies. A few INS variants appear to have distinct mechanisms affecting properties such as protein stability and/or binding to the insulin receptor. Patients with these variants appear more likely to be diagnosed with diabetes in adolescence or early adulthood and may respond to oral hypoglycemic agents (PMID: 18192540). Numerous variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of case-level and experimental data: 17.6 points. Variants in this gene have been reported in at least 11 probands in 7 publications (PMIDs: 17855560, 25721872, 816250, 20007936, 18192540, 19900242, 30182532, 28992123). Variants in this gene segregated with disease in 11 additional family members. A score of 11.6 was achieved for genetic data. This gene-disease association is supported by expression studies, animal models, and in vitro functional assays. In summary, INS is definitively associated with autosomal dominant monogenic 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 INS-related disease entities. Therefore, we have split curations for these disease entities. The present curation includes (1) autosomal dominant monogenic diabetes mellitus, which most often presents in infancy and is usually referred to as permanent neonatal diabetes (MIM: 606176), but may also occur in patients with antibody-negative type 1 diabetes in early childhood, or rarely in adolescence or young adulthood and may be referred to as maturity-onset diabetes of the young 10, (MODY10, MIM:613370). Other entities requiring separate curations include (2) Autosomal recessive diabetes mellitus (usually permanent neonatal; MIM: 606176) and (3) 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.