Genetic testing in inherited endocrine disorders: joint position paper of the European reference network on rare endocrine conditions (Endo-ERN)

Abstract

Background: With the development of molecular high-throughput assays (i.e. next generation sequencing), the knowledge on the contribution of genetic and epigenetic alterations to the etiology of inherited endocrine disorders has massively expanded. However, the rapid implementation of these new molecular tools in the diagnostic settings makes the interpretation of diagnostic data increasingly complex.

Main body: This joint paper of the ENDO-ERN members aims to overview chances, challenges, limitations and relevance of comprehensive genetic diagnostic testing in rare endocrine conditions in order to achieve an early molecular diagnosis. This early diagnosis of a genetically based endocrine disorder contributes to a precise management and helps the patients and their families in their self-determined planning of life. Furthermore, the identification of a causative (epi)genetic alteration allows an accurate prognosis of recurrence risks for family planning as the basis of genetic counselling. Asymptomatic carriers of pathogenic variants can be identified, and prenatal testing might be offered, where appropriate.

Conclusions: The decision on genetic testing in the diagnostic workup of endocrine disorders should be based on their appropriateness to reliably detect the disease-causing and -modifying mutation, their informational value, and cost-effectiveness. The future assessment of data from different omic approaches should be embedded in interdisciplinary discussions using all available clinical and molecular data.

Keywords: Genetic testing; Imprinting disorders; Rare endocrine conditions; Short stature - glucose and insulin homeostasis - Hypogonadotropic hypogonadism - differences/disorders of sex development.

Fig. 1

Molecular diagnostic workup in endocrine diseases. Genetic testing should be based on a comprehensive clinical diagnostic workup as a detailed phenotypic description both of clinical as well as endocrine laboratory features is key to the accuracy and yield of molecular testing. If possible, a targeted testing strategy should be preferred to avoid incidental findings. However, for very heterogeneous disorders WES-based approaches are suitable (for examples see Table 1)

Fig. 2

Example of filtering of genomic variants obtained by whole exome sequencing to identify a pathogenic variant in a growth retarded patientn. By applying different filter parameters like variant frequencies, pathogenicity and mode of inheritance, the number of genomic variants can be reduced and the disease-causing variant can be identified (numbers of variants are shown on the y axis)