Prevalence of germline variants in USP8, USP48, CABLES1 and PAM in patients with pituitary adenomas

Approximately 5% of pituitary adenomas (PA) are familial, linked to germline variants in AIP, or syndrome-related genes like MEN1. While somatic GNAS and USP8 variants predominate in specific subtypes, PAM and CABLES1 genes are emerging.

To investigate the prevalence and clinical significance of germline variants in CABLES1, USP8, USP48, and PAM in patients with PA without established predisposition gene variants.

We analyzed germline DNA from 346 unrelated patients (mostly diagnosed <35 years) with isolated familial or sporadic PA, using a panel targeting CABLES1, USP8, USP48, and PAM. After excluding 20 with variants in known predisposition genes (MEN1, AIP, CDKN1B, PRKAR1A, SDHB, SDHC, SDHD, GNAS, DICER1), 326 patients remained for analysis. Variant interpretation followed American College of Medical Genetics and Genomics criteria with population frequencies, in silico prediction and segregation analysis. We analyzed tumor DNA from 2 cases to assess loss of heterozygosity (LOH).

Uncommon heterozygous germline variants were identified in 30 patients (9.2%), all clinically sporadic. Most variants were classified as benign or of uncertain significance (VUS). Several variants, including USP8 c.104+3A>G, USP48 p.(Pro361Thr), p.(Tyr927Cys) and c.2884 3C>T, and CABLES1 p.(Glu178Lys), were enriched compared with gnomAD frequencies. CABLES1 variants were predominant in macroprolactinomas, USP48 in nonfunctioning PA, and USP8 in prolactinomas and somatotropinomas. No significant genotype-phenotype associations emerged. Familial testing revealed unaffected carriers and LOH was not detected.

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.