Severe early-onset obesity
Gene: ADCY3
Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants of this gene to obesity and this gene can be promoted to green rating at the next major update.
The phenotypes of biallelic variants appear severe and early-onset. The age of patients with monoallelic variants ranged from 28 and 57 and its was not clear whether the patients had either monogenic or common form of obesity. Hence, the MOI should be set as "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal".Created: 1 Sep 2023, 9:22 a.m. | Last Modified: 1 Sep 2023, 9:35 a.m.
Panel Version: 4.7
PMID:29311636 - Founder canonical splice variant (c.2433-1G>A) reported in Greenlandic populations demonstrate higher risk of obesity and type 2 diabetes in homozygous individuals.
PMID:29311637 - Four children from three consanguineous Pakistani families were reported with severe early-onset obesity and identified with three different homozygous variants in ADCY3 gene. In addition, an obese boy of European-American descent was identified with heterozygous ADCY3 variants.
PMID:35026759 - Two additional heterozygous variants (c.1658C>T/ p.Ala553Val & c.489C>G/ p.His163Gln) were identified in six Qatari individuals with obesity. However, the authors of this publication struggle to draw a conclusion on the impact of the dominant effect of the variants due to the genetic and biological overlap between monogenic and the common form of obesity.
Autosomal recessive variants in this gene have been associated with phenotype in OMIM (MIM #617885). But, dominant variants have not yet been associated with relevant phenotypes in OMIM.Created: 31 Aug 2023, 5:57 p.m. | Last Modified: 1 Sep 2023, 9:15 a.m.
Panel Version: 4.5
Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes
{Obesity, susceptibility to, BMIQ19}, OMIM:617885
Publications
Multiple idependet cases reported with early onset severe obesity and LoF variants ir ADCY3.
Sources: LiteratureCreated: 12 Feb 2023, 4:54 p.m.
Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes
Monogenic severe obesity
Publications
Gene: adcy3 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: ADCY3 were changed from Monogenic severe obesity to Monogenic severe obesity; {Obesity, susceptibility to, BMIQ19}, OMIM:617885
Publications for gene: ADCY3 were set to 2931163; 29311637; 35026759
Publications for gene: ADCY3 were set to 29311637; 35026759
Tag Q3_23_promote_green tag was added to gene: ADCY3.
gene: ADCY3 was added gene: ADCY3 was added to Severe early-onset obesity. Sources: Literature Mode of inheritance for gene: ADCY3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: ADCY3 were set to 29311637; 35026759 Phenotypes for gene: ADCY3 were set to Monogenic severe obesity Penetrance for gene: ADCY3 were set to unknown Review for gene: ADCY3 was set to GREEN