Novel THAP1 missense variant with incomplete penetrance in a case of generalized young onset dystonia showing good response to deep brain stimulation

Ignacio J. Keller Sarmiento; Avram Fraint; Lisa Kinsley; Rizwan S. Akhtar; Vincenzo Silani; Steven J. Lubbe; Dimitri Krainc; Niccolò E. Mencacci

doi:10.1016/j.parkreldis.2022.10.022

Novel THAP1 missense variant with incomplete penetrance in a case of generalized young onset dystonia showing good response to deep brain stimulation

Ignacio J. Keller Sarmiento, Avram Fraint, Lisa Kinsley, Rizwan S. Akhtar, Vincenzo Silani, Steven J. Lubbe, Dimitri Krainc, Niccolò E. Mencacci^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Letter › peer-review

Abstract

We describe a case of young onset generalized dystonia, harboring a previously unreported likely pathogenic THAP1 missense variant (c.109 G > A; p.Glu37Lys) that was inherited from her unaffected father. Moreover, we report a positive effect of deep brain stimulation, particularly on the cervical component of dystonia.

Original language	English (US)
Pages (from-to)	7-8
Number of pages	2
Journal	Parkinsonism and Related Disorders
Volume	105
DOIs	https://doi.org/10.1016/j.parkreldis.2022.10.022
State	Published - Dec 2022

Funding

N.E.M. is funded by a Parkinson's Foundation grant. I.J.K.S. is supported by the Align Sience Across Parkinson's (ASAP) Global Parkinson's Genetics Program (GP2). To investigate a possible genetic etiology, an extensive panel for dystonia was ordered, which identified a previously unreported variant in THAP1 (NM_018105.2; exon 2 c.109 G > A; p.Glu37Lys), inherited from her unaffected father. Only one carrier (1/125,682) is reported in the genome aggregation database (gnomAD v2.1.1; https://gnomad.broadinstitute.org/). Whole-exome sequencing was additionally performed as reported elsewhere [3]. This analysis excluded additional relevant pathogenic variants in an extended list of genes linked to movement disorders or other de novo or bi-allelic variants in novel candidate disease-associated genes (Supplemental Table 1). According to ACMG/AMP guidelines, this variant is classified as likely pathogenic, meeting 2 moderate evidence (PM1, PM2) and 2 supporting evidence criteria (PP3, PP4) [4].V.S. received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb S.r.l., Novartis Pharma AG and Zambon. Receives or has received research supports form the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call. He is in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, Frontiers in Neurology.N.E.M. is funded by a Parkinson's Foundation grant.

Keywords

Deep brain stimulation
Generalized dystonia
Incomplete penetrance
Pathogenic variant
THAP1

ASJC Scopus subject areas

Neurology
Geriatrics and Gerontology
Clinical Neurology

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10.1016/j.parkreldis.2022.10.022

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Keller Sarmiento, I. J., Fraint, A., Kinsley, L., Akhtar, R. S., Silani, V., Lubbe, S. J., Krainc, D., & Mencacci, N. E. (2022). Novel THAP1 missense variant with incomplete penetrance in a case of generalized young onset dystonia showing good response to deep brain stimulation. Parkinsonism and Related Disorders, 105, 7-8. https://doi.org/10.1016/j.parkreldis.2022.10.022

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title = "Novel THAP1 missense variant with incomplete penetrance in a case of generalized young onset dystonia showing good response to deep brain stimulation",

abstract = "We describe a case of young onset generalized dystonia, harboring a previously unreported likely pathogenic THAP1 missense variant (c.109 G > A; p.Glu37Lys) that was inherited from her unaffected father. Moreover, we report a positive effect of deep brain stimulation, particularly on the cervical component of dystonia.",

keywords = "Deep brain stimulation, Generalized dystonia, Incomplete penetrance, Pathogenic variant, THAP1",

author = "{Keller Sarmiento}, {Ignacio J.} and Avram Fraint and Lisa Kinsley and Akhtar, {Rizwan S.} and Vincenzo Silani and Lubbe, {Steven J.} and Dimitri Krainc and Mencacci, {Niccol{\`o} E.}",

note = "Funding Information: N.E.M. is funded by a Parkinson's Foundation grant. Funding Information: I.J.K.S. is supported by the Align Sience Across Parkinson's (ASAP) Global Parkinson's Genetics Program (GP2). Funding Information: To investigate a possible genetic etiology, an extensive panel for dystonia was ordered, which identified a previously unreported variant in THAP1 (NM_018105.2; exon 2 c.109 G > A; p.Glu37Lys), inherited from her unaffected father. Only one carrier (1/125,682) is reported in the genome aggregation database (gnomAD v2.1.1; https://gnomad.broadinstitute.org/). Whole-exome sequencing was additionally performed as reported elsewhere [3]. This analysis excluded additional relevant pathogenic variants in an extended list of genes linked to movement disorders or other de novo or bi-allelic variants in novel candidate disease-associated genes (Supplemental Table 1). According to ACMG/AMP guidelines, this variant is classified as likely pathogenic, meeting 2 moderate evidence (PM1, PM2) and 2 supporting evidence criteria (PP3, PP4) [4].V.S. received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb S.r.l., Novartis Pharma AG and Zambon. Receives or has received research supports form the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call. He is in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, Frontiers in Neurology.N.E.M. is funded by a Parkinson's Foundation grant. Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",

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T1 - Novel THAP1 missense variant with incomplete penetrance in a case of generalized young onset dystonia showing good response to deep brain stimulation

AU - Keller Sarmiento, Ignacio J.

AU - Fraint, Avram

AU - Kinsley, Lisa

AU - Akhtar, Rizwan S.

AU - Silani, Vincenzo

AU - Lubbe, Steven J.

AU - Krainc, Dimitri

AU - Mencacci, Niccolò E.

N1 - Funding Information: N.E.M. is funded by a Parkinson's Foundation grant. Funding Information: I.J.K.S. is supported by the Align Sience Across Parkinson's (ASAP) Global Parkinson's Genetics Program (GP2). Funding Information: To investigate a possible genetic etiology, an extensive panel for dystonia was ordered, which identified a previously unreported variant in THAP1 (NM_018105.2; exon 2 c.109 G > A; p.Glu37Lys), inherited from her unaffected father. Only one carrier (1/125,682) is reported in the genome aggregation database (gnomAD v2.1.1; https://gnomad.broadinstitute.org/). Whole-exome sequencing was additionally performed as reported elsewhere [3]. This analysis excluded additional relevant pathogenic variants in an extended list of genes linked to movement disorders or other de novo or bi-allelic variants in novel candidate disease-associated genes (Supplemental Table 1). According to ACMG/AMP guidelines, this variant is classified as likely pathogenic, meeting 2 moderate evidence (PM1, PM2) and 2 supporting evidence criteria (PP3, PP4) [4].V.S. received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb S.r.l., Novartis Pharma AG and Zambon. Receives or has received research supports form the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call. He is in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, Frontiers in Neurology.N.E.M. is funded by a Parkinson's Foundation grant. Publisher Copyright: © 2022 Elsevier Ltd

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N2 - We describe a case of young onset generalized dystonia, harboring a previously unreported likely pathogenic THAP1 missense variant (c.109 G > A; p.Glu37Lys) that was inherited from her unaffected father. Moreover, we report a positive effect of deep brain stimulation, particularly on the cervical component of dystonia.

AB - We describe a case of young onset generalized dystonia, harboring a previously unreported likely pathogenic THAP1 missense variant (c.109 G > A; p.Glu37Lys) that was inherited from her unaffected father. Moreover, we report a positive effect of deep brain stimulation, particularly on the cervical component of dystonia.

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KW - Incomplete penetrance

KW - Pathogenic variant

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ER -

Novel THAP1 missense variant with incomplete penetrance in a case of generalized young onset dystonia showing good response to deep brain stimulation

Abstract

Funding

Keywords

ASJC Scopus subject areas

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