Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis

Gene: STX16

I don't know

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GMS reviewers commented as follows: Only STX16 deletions are clinically relevant and STX16 probes are included in the MS-MLPA kit which is an essential component of R293 testing as STX16 deletions act on methylation only. Adding this gene to Panelapp could be missleading as would suggest analysis of SNVs.

Created: 10 Dec 2025, 2:07 p.m. | Last Modified: 10 Dec 2025, 2:07 p.m.

Panel Version: 1.6

Comment on list classification: There is sufficient evidence available for the association of STX16 deletions with Pseudohypoparathyroidism Ib (MIM #603233). As reviewed by Treena Cranston on Familial hypoparathyroidism panel (please see her review below, which was copied from that panel), the pseudohypoparathyroidism phenotype should be covered by this panel (R293) rather than R153. Hence, this gene should be considered for promotion to green rating on this panel in the next GMS update.

Created: 24 Jun 2025, 9:58 a.m. | Last Modified: 24 Jun 2025, 9:58 a.m.

Panel Version: 1.4

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, 9:51 a.m. | Last Modified: 24 Jun 2025, 9:51 a.m.

Panel Version: 1.3

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

Phenotypes
Pseudohypoparathyroidism Ib, OMIM:603233

I don't know

I would rate this as an amber gene (although currently red if applying the R153 eligibility criteria; but given these sometimes change amber would be appropriate).
STX16 deletions are associated with pseudohypoparathroidism (1b) (hypocalcaemia, but appropriately elevated PTH) rather than hypoparathyroidism. R153 eligibility criteria require hypocalcaemia AND low or inappropriately normal serum PTH and therefore these STX16 deletion patients would not fulfill the eligibility criteria. Instead this is appropriately covered by the R293 panel.

Created: 27 Feb 2025, 3:44 p.m. | Last Modified: 27 Feb 2025, 3:44 p.m.

Panel Version: 2.17

I don't know

The rating of this gene has was initially changed to green (but not in the signed off version of the panel) but after further review it has been decided to keep it as amber (see review by Treena Cranston) . The clinical phenotype of pseudohypoparathroidism 1b does not fit with the testing criteria of the panel: R153 requires hypocalcaemia and low PTH levels (/ inappropriately normal in ADH) due to defective PTH production in the main) - so patients with STX16 wont clinically fulfil R153 test criteria.

Therefore this gene remains amber following NHS Genomic Medicine Service review.

Created: 6 Dec 2024, 1:11 p.m. | Last Modified: 4 Mar 2025, 12:11 p.m.

Panel Version: 2.18

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

When the copy number coordinates have been established by ClinGen for STX16, this information will be added to the Familial hypoparathyroidism panel

Created: 1 Nov 2022, 12:53 p.m. | Last Modified: 1 Nov 2022, 12:53 p.m.

Panel Version: 2.7

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 13 Oct 2022, 11:48 a.m. | Last Modified: 13 Oct 2022, 11:48 a.m.

Panel Version: 2.7

Comment on mode of inheritance: STX16 is expressed from both alleles and so is not imprinted. However, maternally inherited STX16 variants have been reported in pseudohypoparathyroidism type 1B, which appear to have a cis disrupting effect on GNAS Exon A/B transcript (PMID: 14561710; 15579741; 15800843; 33320452; 32337648; 35119251).

Created: 13 Oct 2022, 11:34 a.m. | Last Modified: 13 Oct 2022, 11:34 a.m.

Panel Version: 0.147

At least five unrelated cases of Pseudohypoparathyroidism, type IB have been reported with a maternally inherited deletion ranging from 3 - 87.5 kb, encompassing some or all of the exons of STX16. The result effect of these deletions is thought to be the disruption of cis-acting control elements of imprinting, which are necessary for establishing and/or maintaining methylation at GNAS exon A/B, including..
Sources: Literature

Created: 4 Jan 2021, 3:29 p.m. | Last Modified: 11 Oct 2022, 10:17 a.m.

Panel Version: 0.144

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Pseudohypoparathyroidism, type IB OMIM:603233; pseudohypoparathyroidism type 1B:MONDO:0011301

Publications

• 14561710
• 15579741
• 15800843
• 33320452
• 32337648