Landscape of genetic testing in MCT8-deficiency

Background: MCT8-deficiency is an ultrarare X-linked genetic disease caused by mutations in the SLC16A2 gene. Owing to its rarity and heterogeneity of clinical manifestations, diagnosis can be missed if SLC16A2 is not included in multigene panels.

Case study / Methods: In November 2022, we searched Orphanet (Europe) and the NIH Genetic Testing Registry (USA), to identify laboratories offering genetic testing for SLC16A2. Laboratory websites were examined for supplementary information and contacted for verification of current data obtained from databases.

Results: Genetic testing is strictly regulated and exclusively conducted by government-approved (academic) hospital laboratories in the Netherlands (NL), Belgium (B) and France (F). The UK has a centralized approach across seven Genomic Laboratory Hubs. Germany (D) and the USA primarily utilize commercial laboratories for testing for SLC16A2. Confirmation response rate was highest in NL and lowest in Italy (It) and Spain (Sp). SLC16A2 is mostly included in panels for Intellectual disability (ID) and spastic paraplegia (SP). ID is the most offered panel in NL (6/7 centers), B (5/8), F (18/24) and Spain (6/12); SD in D (5/11), It (3/6) and USA (9/19). Variability exists in the inclusion of SLC16A2 in the epilepsy panel in NL, B, and Sp. Panels for leukodystrophy/-encephalopathy and autism, including SLC16A2, are frequently offered in USA, less commonly in most European countries. In NL, SLC16A2 was absent in 3/5 labs offering panels related to endocrine or metabolic disorders. Commercial laboratories generally offer a wider range of panels, with SLC16A2 frequently included. Most laboratories were willing to discuss adding SLC16A2 to relevant panels.

Discussion/Conclusion: This overview of current multigene panels can help guide expert groups and patient advocacy organizations in improving diagnostic opportunities for early MCT8-deficiency detection.