Lipodystrophy - childhood onset
Gene: AKT2
Comment on list classification: Two unrelated cases and supporting functional evidence from mouse models suggest that this gene can be promoted to green rating in the next GMS review.Created: 2 Aug 2023, 6:16 p.m. | Last Modified: 2 Aug 2023, 6:16 p.m.
Panel Version: 4.9
PMID:15166380 - A missense variant (p.Arg274His) in AKT2 gene was identified in a family with autosomal dominant severe insulin resistance, diabetes mellitus and partial lipodystrophy.
PMID:17327441 - Of 94 probands with severe insulin resistance (35 of which had partial lipodystrophy) that were screened for AKT2 variants, one female identified with p.Arg467Trp variant was reported with type 2 diabetes and partial lipodystrophy, while another female identified with p.Arg208Lys variant had severe insulin resistance and acanthosis nigricans. p.Arg467Trp was present in neither 47 ethnically matched control subjects nor in 2 unaffected sons of the carrier. p.Arg208Lys variant was not present in her affected son but was present in 1 of 47 white control subjects.
PMID:12843127 - Functional studies in mice showed that loss of AKT2 results in severe diabetes, age-dependent lipoatrophy and mild growth deficiency.Created: 2 Aug 2023, 6:14 p.m. | Last Modified: 2 Aug 2023, 6:14 p.m.
Panel Version: 4.6
This review was provided by NHSE Genomic Medicine Service for inclusion of this gene in this panel:
A causal role for a R274H variant in Akt2 was demonstrated here PMID: 15166380, where the variant co-segregated with severe insulin resistance, partial lipodystrophy and type 2 diabetes. Akt2 knockout mice develop an analogous age-dependent partial lipoatrophy (PMID: 12843127), and Akt2 is a canonical effector of insulin signalling. Akt2 is currently analysed and reported as part of assessment for Monogenic diabetes (R141) on the strength of this evidence. It has been endorsed as a cause of lipodystrophy by an international multi-society practice guideline (PMID: 27710244)Created: 2 Aug 2023, 11:38 a.m. | Last Modified: 2 Aug 2023, 11:38 a.m.
Panel Version: 4.3
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Severe insulin resistance, familial partial lipodystrophy
Publications
Comment when marking as ready: AKT2 was included in the gene list as suggested by Kevin Colclough (Royal Devon & Exeter Hospital). AKT2 is a red gene in the Insulin resistance (including lipodystrophy) (Version 1.6) panel and only 1 variant has been reported when this gene was reviewed for that panel (2016). There has not been any new variants for this gene.Created: 7 Jan 2019, 11:21 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Comment when marking as ready: Associated with phenotype in OMIM, not in G2P. Only one LOF variant reportedCreated: 12 Aug 2016, 3:13 p.m.
Comment on publications: 17327441 questions relevance of AKT2 LOF variants for type 2 diabetes risk, while 11387480 examining a mouse model supports the involvement of AKT in normal glucose homeostasis.Created: 12 Aug 2016, 3:04 p.m.
Comment on phenotypes: Also associated with Hypoinsulinemic hypoglycemia with hemihypertrophy 240900Created: 11 Aug 2016, 1 p.m.
Gene: akt2 has been classified as Amber List (Moderate Evidence).
Publications for gene: AKT2 were set to 15166380; 17327441
Mode of inheritance for gene: AKT2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Tag Q3_23_promote_green tag was added to gene: AKT2. Tag Q3_23_NHS_review tag was added to gene: AKT2.
Phenotypes for gene: AKT2 were changed from Diabetes mellitus, type II, 125853; Hypoinsulinemic hypoglycemia with hemihypertrophy, 240900; Partial lipodystrophy to Diabetes mellitus, type II, OMIM:125853; Type 2 diabetes mellitus, MONDO:0005148; Hypoinsulinemic hypoglycemia with hemihypertrophy, OMIM:240900; Hypoinsulinemic hypoglycemia and body hemihypertrophy, MONDO:0009416; Partial lipodystrophy
Sarah Leigh: Comment on phenotypes: Also as
Gene: akt2 has been classified as Red List (Low Evidence).
Gene: akt2 has been classified as Red List (Low Evidence).
Publications for gene: AKT2 were set to
Phenotypes for gene: AKT2 were changed from Diabetes mellitus, type II, 125853; Hypoinsulinemic hypoglycemia with hemihypertrophy, 240900 to Diabetes mellitus, type II, 125853; Hypoinsulinemic hypoglycemia with hemihypertrophy, 240900; Partial lipodystrophy
Phenotypes for gene: AKT2 were changed from Diabetes mellitus, type II, 125853 to Diabetes mellitus, type II, 125853; Hypoinsulinemic hypoglycemia with hemihypertrophy, 240900
gene: AKT2 was added gene: AKT2 was added to Lipodystrophy - childhood onset. Sources: Expert list Mode of inheritance for gene: AKT2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: AKT2 were set to Diabetes mellitus, type II, 125853