Prevalence of germline variants in USP8, USP48, CABLES1 and PAM in patients with pituitary adenomas
Authors' conclusion
No (likely) pathogenic germline variants were identified. While most were benign or VUS, specific variants-most notably in USP48-showed nominal enrichment compared to gnomAD frequencies, which might suggest a potential low-penetrance susceptibility or modifier effect that will require further validation. This work primarily focused on PAM, CABLES1, USP8, and USP48, but other germline or somatic variants may also contribute. Clinical management and genetic counseling should not be guided by benign variants or VUS.
Study context
- Population
- Unrelated patients (mostly diagnosed <35 years) with isolated familial or sporadic pituitary adenomas (PA), without variants in known predisposition genes326 analysed
- Participants
- 346 patients
- Outcome
- Prevalence and clinical significance of germline variants in CABLES1, USP8, USP48 and PAM
Methodological detailspanel sequencing of germline DNA, ACMG variant interpretation, segregation analysis, tumor loss of heterozygosity (LOH) analysis in 2 cases
- Panel sequencing of germline DNA
- ACMG variant interpretation
- Segregation analysis
- Tumor LOH analysis in 2 cases
Main finding
As reported in the abstract
Patients with uncommon heterozygous germline variants, all clinically sporadic
30
9.2%
Further findings
Genotype-phenotype associations
- CABLES1 variants predominant in macroprolactinomas, USP48 in nonfunctioning PA, USP8 in prolactinomas and somatotropinomas; no significant genotype-phenotype associations
Familial testing and LOH
- Familial testing revealed unaffected carriers; LOH not detected
Original publication
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