Severe early-onset obesity

Gene: ADCY3

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 4 Dec 2024, 9:27 p.m. | Last Modified: 4 Dec 2024, 9:27 p.m.

Panel Version: 4.12

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

• 29311636
• 29311637
• 35026759

Green List (high evidence)

Multiple idependet cases reported with early onset severe obesity and LoF variants ir ADCY3.
Sources: Literature

Created: 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

• 29311637
• 35026759