Severe early-onset obesity

Gene: TRPC5

I don't know

PMID:38959890 reported the identification of micrdeletions disrupting TRPC5 gene in two unrelated boys with severe obesity. Both probands also had brothers who had severe obesity and carried the same deletion, which was inherited from their mothers who also had obesity. This suggests that the mode of inheritance is X-linked dominant.

The male patients exhibited syndromic phenotype, presenting with extreme food-seeking and hoarding behaviour, obesity, anxiety and/ or depression, attention problems, and autism. These phenotypes were recapitulated in knock-in male mice harbouring a human loss-of-function TRPC5 variant.

Women carrying TRPC5 deletions had severe postpartum depression. Female knock-in mice exhibited anhedonia and depression-like behaviour with impaired care of offspring.

As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf) the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years. In addition, this panel is intended for patients without significant syndromic features.

Although the above probands had BMI >3 SDs above the mean at the age of evaluation (14.4 and 17.2 years), the publication does not state the age of onset of obesity and/ or severity at the age of onset. In addition, the presenting phenotypes were syndromic.

Hence, this gene cannot be rated green with current evidence and should be rated amber instead.

Created: 16 Jun 2025, 4:43 p.m. | Last Modified: 16 Jun 2025, 4:43 p.m.

Panel Version: 5.4

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Obesity, HP:0001513

Publications

• 38959890

Green List (high evidence)

The study describes multiple individuals with TRPC5 pathogenic variants (deletions and missense) with functional validation of missense and mouse model: Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression.
Sources: Literature

Created: 24 Aug 2024, 11:50 p.m. | Last Modified: 24 Aug 2024, 11:51 p.m.

Panel Version: 4.10

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
obesity

Publications

• PMID: 38959890