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

Sabine Grønborg; Lotte Risom; Jakob Ek; Karen Bonde Larsen; David Scheie; Yanko Petkov; Vibeke André Larsen; Morten Dunø; Fróði Joensen; Elsebet Østergaard

doi:10.1038/s41431-018-0204-5

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

Sabine Grønborg^*, Lotte Risom, Jakob Ek, Karen Bonde Larsen, David Scheie, Yanko Petkov, Vibeke André Larsen, Morten Dunø, Fróði Joensen, Elsebet Østergaard

^*Corresponding author for this work

Department of Clinical Medicine

3 Citations (Scopus)

Abstract

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-tubulin heterodimer. Recently, variants in TBCD, and one other tubulin-specific chaperone, TBCE, have been identified in patients with distinct progressive encephalopathy with a seemingly broad clinical spectrum. Here, we report the clinical, neuroradiological, and neuropathological features in eight patients originating from the Faroe Islands, who presented with an early onset, progressive encephalopathy with 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 Faroese population (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 Faroese phenotype. We present a detailed description of the neuropathology and MR imaging characteristics of a subset of these patients, adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroese founder variant will allow targeted genetic diagnostics in patients of Faroese descent as well as improved genetic counseling and testing of at-risk couples.

Original language	English
Journal	European Journal of Human Genetics
Volume	26
Issue number	10
Pages (from-to)	1512-1520
Number of pages	9
ISSN	1018-4813
DOIs	https://doi.org/10.1038/s41431-018-0204-5
Publication status	Published - 2018

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@article{44c5d3e3b9a946d0bf41f1894fadb36b,

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

abstract = "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-tubulin heterodimer. Recently, variants in TBCD, and one other tubulin-specific chaperone, TBCE, have been identified in patients with distinct progressive encephalopathy with a seemingly broad clinical spectrum. Here, we report the clinical, neuroradiological, and neuropathological features in eight patients originating from the Faroe Islands, who presented with an early onset, progressive encephalopathy with 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 Faroese population (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 Faroese phenotype. We present a detailed description of the neuropathology and MR imaging characteristics of a subset of these patients, adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroese founder variant will allow targeted genetic diagnostics in patients of Faroese descent as well as improved genetic counseling and testing of at-risk couples.",

author = "Sabine Gr{\o}nborg and Lotte Risom and Jakob Ek and Larsen, {Karen Bonde} and David Scheie and Yanko Petkov and Larsen, {Vibeke Andr{\'e}} and Morten Dun{\o} and Fr{\'o}{\dh}i Joensen and Elsebet {\O}stergaard",

year = "2018",

doi = "10.1038/s41431-018-0204-5",

language = "English",

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T1 - A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course

AU - Grønborg, Sabine

AU - Risom, Lotte

AU - Ek, Jakob

AU - Larsen, Karen Bonde

AU - Scheie, David

AU - Petkov, Yanko

AU - Larsen, Vibeke André

AU - Dunø, Morten

AU - Joensen, Fróði

AU - Østergaard, Elsebet

PY - 2018

Y1 - 2018

N2 - 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-tubulin heterodimer. Recently, variants in TBCD, and one other tubulin-specific chaperone, TBCE, have been identified in patients with distinct progressive encephalopathy with a seemingly broad clinical spectrum. Here, we report the clinical, neuroradiological, and neuropathological features in eight patients originating from the Faroe Islands, who presented with an early onset, progressive encephalopathy with 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 Faroese population (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 Faroese phenotype. We present a detailed description of the neuropathology and MR imaging characteristics of a subset of these patients, adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroese founder variant will allow targeted genetic diagnostics in patients of Faroese descent as well as improved genetic counseling and testing of at-risk couples.

AB - 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-tubulin heterodimer. Recently, variants in TBCD, and one other tubulin-specific chaperone, TBCE, have been identified in patients with distinct progressive encephalopathy with a seemingly broad clinical spectrum. Here, we report the clinical, neuroradiological, and neuropathological features in eight patients originating from the Faroe Islands, who presented with an early onset, progressive encephalopathy with 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 Faroese population (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 Faroese phenotype. We present a detailed description of the neuropathology and MR imaging characteristics of a subset of these patients, adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroese founder variant will allow targeted genetic diagnostics in patients of Faroese descent as well as improved genetic counseling and testing of at-risk couples.

U2 - 10.1038/s41431-018-0204-5

DO - 10.1038/s41431-018-0204-5

M3 - Journal article

C2 - 29921875

AN - SCOPUS:85048707800

SN - 1018-4813

VL - 26

SP - 1512

EP - 1520

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 10

ER -

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

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