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Studies involving STX16 (HGNC:11431) have consistently demonstrated its strong association with pseudohypoparathyroidism (MONDO_0019992), particularly the autosomal dominant type 1B form. Multiple independent case reports have identified recurrent deletions in STX16, such as the documented 3‑kb deletion and exon 5‑7 deletion events, where affected individuals present with biochemical hallmarks of parathyroid hormone resistance and characteristic phenotypes such as macrosomia, macrocephaly, and hypocalcemia (PMID:27338644).
Genetic studies have revealed that these deletions in STX16 disrupt the normal methylation and imprinting at the GNAS locus, leading to an autosomal dominant pattern of inheritance. Familial segregation has been observed in several reports, with affected relatives (e.g., a proband’s mother and monozygotic twins) carrying the deletion and manifesting related endocrine abnormalities (PMID:39026465)
In-depth genetic analyses across case series have documented numerous probands — totaling over 40 individuals across independent studies — presenting with STX16 deletions. These findings include recurrent deletion events in different exonic regions that show clear segregation with the disease phenotype and correlate with clinical parameters such as hypocalcemia, hyperphosphatemia, and other hormone resistance features (PMID:32337648).
Functional assessments provide further support for the pathogenicity of STX16 deletions. Experimental data have demonstrated that loss of STX16 function leads to abnormal epigenetic regulation of the GNAS complex. Cellular studies and methylation assays have confirmed impaired imprinting mechanisms, offering a molecular explanation for the PTH resistance and other endocrine abnormalities observed in patients (PMID:26479409).
Although some investigations have emphasized the broader spectrum of GNAS imprinting defects, the reproducibility of STX16 deletion findings across multiple case reports and familial studies makes a compelling argument for its role in pseudohypoparathyroidism. No significant conflicting data have been reported that would weaken the association, thus bolstering the clinical validity of this genetic marker.
In summary, the convergence of clinical, genetic, and functional evidence indicates a strong gene‑disease relationship between STX16 deletions and pseudohypoparathyroidism. This robust association supports informed diagnostic decision‑making, targeted genetic counseling, and may guide future therapeutic strategies. Key take‑home sentence: STX16 deletions represent a reliable genetic marker for autosomal dominant pseudohypoparathyroidism type 1B, offering significant clinical utility for risk assessment and personalized management.
Gene–Disease AssociationStrongOver 40 probands across independent studies with consistent STX16 deletion findings, familial segregation, and demonstration of epigenetic disruption at the GNAS locus (PMID:27338644, PMID:32337648). Genetic EvidenceStrongMultiple probands exhibiting recurrent STX16 deletions with autosomal dominant inheritance and clear familial segregation (PMID:39026465, PMID:25843330). Functional EvidenceModerateFunctional studies revealing that STX16 deletions lead to abnormal GNAS imprinting and consequent hormone resistance, supporting the pathogenic mechanism (PMID:26479409, PMID:17595244). |