Severe early-onset obesity

Gene: STX16

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.

Created: 11 Dec 2025, 4:59 p.m. | Last Modified: 11 Dec 2025, 4:59 p.m.

Panel Version: 5.20

Green List (high evidence)

Comment on mode of inheritance: STX16 is not clearly an imprinted gene. As reported in publications, only maternally inherited deletions are associated with this phenotype. Deletions in this gene are thought to disrupt cis-acting regulation of GNAS expression.

Created: 24 Jun 2025, 9:49 a.m. | Last Modified: 24 Jun 2025, 9:49 a.m.

Panel Version: 5.18

PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion.

PMID:28453643 reported five patients reported with obesity with onset ranging from 3-12 months of age. Deletion of STX16 gene (either 3-kb or 4.4-kb) was reported in these cases confirming genetic diagnosis of Pseudohypoparathyroidism, type IB. All these patients inherited STX16 deletions from their unaffected mothers, and these deletions reside on paternal allele of these mothers. This indicates that maternally inherited deletions are associated with the phenotype. Excessive weight gain preceded other clinical or laboratory signs of PHP1B by more than a decade in some patients. One of these patients had symptomatic hypocalcemia and elevated PTH levels when admitted to hospital at 11.5 years, and another was reported with asymptomatic hypocalcemia and an elevated PTH level only after establishing the genetic defect.

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 and in the absence of significant features.

All the cases reported above had early onset obesity before the age of 5 and appears severe. However, the patient from PMID:27338644 had other presentations such as macrosomia and macrocephaly suggesting the phenotype is syndromic. Although some of the cases reported in PMID:28453643 had hypocalcemia and an elevated PTH level, their onset was much later than that of obesity. Hence, it is useful to include this gene on this panel to get diagnosis for patients early in their life and before the onset of PHP1B.

Created: 17 Jun 2025, 7:25 a.m. | Last Modified: 23 Jun 2025, 4:11 p.m.

Panel Version: 5.16

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Pseudohypoparathyroidism, type IB OMIM:603233; Obesity, HP:0001513

Publications

• 27338644
• 28453643

Green List (high evidence)

PMID: 27338644 & PMID: 28453643 shows that STX16 deletions, causing GNAS methylation defects, result in obesity. GNAS is already on this panel as green. Enough evidence for the green rating.
Sources: Literature

Created: 12 Jan 2025, 10:57 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Obesity with pseudohypoparathyroidism type 1B

Publications

• PMID: 27338644
• 28453643