A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course

An intact and dynamic microtubule cytoskeleton is crucial for the development, differentiation, and maintenance of the mammalian cortex. Variants in a host of structural microtubulin-associated proteins have been identified to cause a wide spectrum of malformations of cortical development and alterations of microtubule dynamics have been recognized to cause or contribute to progressive neurodegenerative disorders. TBCD is one of the five tubulin-specific chaperones and is required for reversible assembly of the α-/β- tubulinheterodimer. Recently, variants in TBCD, and one other tubulin-specific chaperone, TBCE, have been identified in patients with distinct progressive encephalopathywith a seemingly broad clinical spectrum. Here, we report the clinical, neuroradiological, and neuropathologicalfeatures in eight patients originating from the Faroe Islands, who presented with an early onset, progressive encephalopathywith features of primary neurodegeneration, and a homogenous clinical course. These patients were homozygous for a TBCD missense variant c.[3099C>G]; p.(Asn1033Lys), which we show has a high carrier frequency in the Faroesepopulation (2.6%). The patients had similar age of onset as the previously reported patients (n = 24), but much shorter survival, which could be caused by either differences in supportive treatment, or alternatively, that shorter survival is intrinsic to the Faroesephenotype. We present a detailed description of the neuropathologyand MR imaging characteristics of a subset of these patients, adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroesefounder variant will allow targeted genetic diagnostics in patients of Faroesedescent as well as improved genetic counseling and testing of at-risk couples.