Abstract
IntroductionAlthough current guidelines prefer the use of targeted testing or small-scale gene panels for identification of genetic susceptibility of hereditary endocrine tumour syndromes, next generation sequencing based strategies have been widely introduced into every day clinical practice. The application of next generation sequencing allows rapid testing of multiple genes in a cost effective manner. Increasing knowledge about these techniques and the demand from health care providers and society, shift the molecular genetic testing towards using high-throughput approaches.PurposeIn this expert opinion, the authors consider the molecular diagnostic workflow step by step, evaluating options and challenges of gathering family information, pre- and post-test genetic counselling, technical and bioinformatical analysis related issues and difficulties in clinical interpretation focusing on molecular genetic testing of hereditary endocrine tumour syndromes.Result and conclusionConsidering all these factors, a diagnostic genetic workflow is also proposed for selection of the best approach for testing of patients with hereditary genetic tumour syndromes in order to minimalize difficult interpretation, unwanted patient anxiety, unnecessary medical interventions and cost. There are potential benefits of utilizing high throughput approaches however, important limitations have to be considered and should discussed towards the clinicians and patients.
Highlights
Current guidelines prefer the use of targeted testing or small-scale gene panels for identification of genetic susceptibility of hereditary endocrine tumour syndromes, generation sequencing based strategies have been widely introduced into every day clinical practice
5 Semmelweis University, Budapest, Hungary genetic diagnostic testing in rare endocrine conditions in order to achieve an early molecular diagnosis [1]. In this present expert opinion, we summarise the currently valid guidelines relevant for molecular genetic diagnostic workflow used in clinical investigation of hereditary endocrine tumour syndromes
Features that suggest genetic susceptibility are: early age of onset, multiple primary tumours, multifocal sites, bilateral tumour appearance in paired organs, same type of tumour in first or second-degree relatives or same tumour type clustering within a family, rare tumour types, and rare tumours associated with birth defects [5]
Summary
A joint position paper of the European Reneference Network on rare endocrine diseases (Endo-ERN) was recently published about genetic testing in inherited endocrine disorders [1]. Screening for hereditary cancer syndromes is only recommended in high-risk patients due to higher VUS rate, the equivocal clinical value of variants with low-penetrance or newly discovered genes and secondary findings [56]. A patient despite having a clear phenotype characteristic for an endocrine tumour syndrome the genetic test fails to identify the pathogenic alteration Selection of the proper test is the task of genetic counsellors after patients are referred to genetic consultation by clinicians (endocrinologist, oncologist) Whenever it is possible (e.g. typical clinical presentation) targeted gene testing (usually by conventional Sanger sequencing and/or MLPA for detection of copy number alteration) is suggested (Fig. 1). If no pathogenic variant is identified but the clinical suspicion is still strong, in atypical cases, or in case of seeking potential low/moderate penetrance genes WES could be performed keeping in mind detection rates and all uncertainties listed above
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