Endocrine Abstracts

Background: Establishing a genetic diagnosis in patients presenting with potential monogenic endocrine disorders can provide benefits for the individual and wider family. Next-generation sequencing (NGS) gene panels provide a time- and cost-efficient platform for testing. A Scottish NGS endocrine testing platform, comprising 30 genes (11 individual panels), was established in 2018. A national genomic test-directory provides eligibility criteria for testing, but these are yet to be evaluated against ‘real world’ referrals.

Methods: Index cases referred for Endocrine NGS gene panel testing (12/2018-12/2022) were evaluated for baseline clinical characteristics, indication for testing and test outcome. Referrals were assessed against national eligibility criteria (v1.0/2022).

Results: 1131 endocrine gene panel requests representing 1057 index cases were identified (>1 panel for some patients), with a mean age of 45 years and a female predominance (~1:2 M:F). Of the most frequently requested panels (Familial Hyperparathyroidism (FHPT) (n=329), Familial Hypocalciuric Hypercalcaemia (FHH) (n=220), Multiple Endocrine Neoplasia1/4/Familial Isolated Pituitary Adenoma (MEN1/4/FIPA) (n=196) and Phaeochromocytoma/Paraganglioma (PPGL) (n=121)), the proportion of index cases with pathogenic/likely pathogenic variants varied markedly (i.e. 5.5%, 22.3%, 3.6%, 18.9%, respectively). Several patients referred for FHPT testing harboured pathogenic CASR variants, consistent with a diagnosis of FHH. Whilst the majority of requests met referral criteria, ~40% of FHH referral contained insufficient/inconsistent biochemical information to assess eligibility. Notably, ~30% of PPGL referrals did not meet testing criteria, including ~10% of cases with a positive genetic test result. Of the more commonly requested panels, PPGL and MEN1/4/FIPA panels were the most and least cost-effective (~£1300 and ~£7000 per positive test, respectively).

Conclusions: Combining panels improves diagnostic yields for disorders with overlapping clinical phenotypes (e.g. FHPT & FHH). Strict enforcement of testing eligibility criteria may result in ‘missed’ genetic diagnoses, the implications of which should be considered when reviewing and/or implementing future test criteria.