TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants

Jennifer N. Dines; Katie Golden-Grant; Amy LaCroix; Alison M. Muir; Dianne Laboy Cintrón; Kirsty McWalter; Megan T. Cho; Angela Sun; J. Lawrence Merritt; Jenny Thies; Dmitriy Niyazov; Barbara Burton; Katherine Kim; Leah Fleming; Rachel Westman; Peter I Karachunski; Joline Dalton; Alice Basinger; Can Ficicioglu; Ingo Helbig; Manuela Pendziwiat; Hiltrud Muhle; Katherine L. Helbig; Almuth Caliebe; René Santer; Kolja Becker; Sharon Suchy; Ganka Douglas; Francisca Millan; Amber Begtrup; Kristin G. Monaghan; Heather C. Mefford

doi:10.1038/s41436-018-0137-y

TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants

Jennifer N. Dines, Katie Golden-Grant, Amy LaCroix, Alison M. Muir, Dianne Laboy Cintrón, Kirsty McWalter, Megan T. Cho, Angela Sun, J. Lawrence Merritt, Jenny Thies, Dmitriy Niyazov, Barbara Burton, Katherine Kim, Leah Fleming, Rachel Westman, Peter I Karachunski, Joline Dalton, Alice Basinger, Can Ficicioglu, Ingo HelbigManuela Pendziwiat, Hiltrud Muhle, Katherine L. Helbig, Almuth Caliebe, René Santer, Kolja Becker, Sharon Suchy, Ganka Douglas, Francisca Millan, Amber Begtrup, Kristin G. Monaghan, Heather C. Mefford

Neurology

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

41 Scopus citations

Abstract

Purpose: TANGO2-related disorders were first described in 2016 and prior to this publication, only 15 individuals with TANGO2-related disorder were described in the literature. Primary features include metabolic crisis with rhabdomyolysis, encephalopathy, intellectual disability, seizures, and cardiac arrhythmias. We assess whether genotype and phenotype of TANGO2-related disorder has expanded since the initial discovery and determine the efficacy of exome sequencing (ES) as a diagnostic tool for detecting variants. Methods: We present a series of 14 individuals from 11 unrelated families with complex medical and developmental histories, in whom ES or microarray identified compound heterozygous or homozygous variants in TANGO2. Results: The initial presentation of patients with TANGO2-related disorders can be variable, including primarily neurological presentations. We expand the phenotype and genotype for TANGO2, highlighting the variability of the disorder. Conclusion: TANGO2-related disorders can have a more diverse clinical presentation than previously anticipated. We illustrate the utility of routine ES data reanalysis whereby discovery of novel disease genes can lead to a diagnosis in previously unsolved cases and the need for additional copy-number variation analysis when ES is performed.

Original language	English (US)
Pages (from-to)	601-607
Number of pages	7
Journal	Genetics in Medicine
Volume	21
Issue number	3
DOIs	https://doi.org/10.1038/s41436-018-0137-y
State	Published - Mar 1 2019

Bibliographical note

Funding Information:
We thank the families, GeneDx, and practitioners for their participation and collaboration in this case series. Research reported in this publication was supported in part by a grant from the National Institutes of Health (NS069605 to H.C.M.), and the National Institute of General Medical Sciences of the National Institutes of Health Postdoctoral Training Program in Medical Genetics (5T32GM007454 to J.N.D.). This work was also supported by intramural funds of the University of Kiel (I.H.), the German Research Foundation (HE5415/3-1 to I.H.) within the EuroEPINOMICS framework of the European Science Foundation, and individual grants by the German Research Foundation (D.F. G., HE5415/5-1, HE5415/6-1 to I.H.).

Publisher Copyright:
© 2018, American College of Medical Genetics and Genomics.

Keywords

developmental delay DNA copy-number variation
epilepsy
exome sequencing
intragenic deletion

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Dines, J. N., Golden-Grant, K., LaCroix, A., Muir, A. M., Cintrón, D. L., McWalter, K., Cho, M. T., Sun, A., Merritt, J. L., Thies, J., Niyazov, D., Burton, B., Kim, K., Fleming, L., Westman, R., Karachunski, P. I., Dalton, J., Basinger, A., Ficicioglu, C., ... Mefford, H. C. (2019). TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants. Genetics in Medicine, 21(3), 601-607. https://doi.org/10.1038/s41436-018-0137-y

Dines, JN, Golden-Grant, K, LaCroix, A, Muir, AM, Cintrón, DL, McWalter, K, Cho, MT, Sun, A, Merritt, JL, Thies, J, Niyazov, D, Burton, B, Kim, K, Fleming, L, Westman, R, Karachunski, PI, Dalton, J, Basinger, A, Ficicioglu, C, Helbig, I, Pendziwiat, M, Muhle, H, Helbig, KL, Caliebe, A, Santer, R, Becker, K, Suchy, S, Douglas, G, Millan, F, Begtrup, A, Monaghan, KG & Mefford, HC 2019, 'TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants', Genetics in Medicine, vol. 21, no. 3, pp. 601-607. https://doi.org/10.1038/s41436-018-0137-y

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abstract = "Purpose: TANGO2-related disorders were first described in 2016 and prior to this publication, only 15 individuals with TANGO2-related disorder were described in the literature. Primary features include metabolic crisis with rhabdomyolysis, encephalopathy, intellectual disability, seizures, and cardiac arrhythmias. We assess whether genotype and phenotype of TANGO2-related disorder has expanded since the initial discovery and determine the efficacy of exome sequencing (ES) as a diagnostic tool for detecting variants. Methods: We present a series of 14 individuals from 11 unrelated families with complex medical and developmental histories, in whom ES or microarray identified compound heterozygous or homozygous variants in TANGO2. Results: The initial presentation of patients with TANGO2-related disorders can be variable, including primarily neurological presentations. We expand the phenotype and genotype for TANGO2, highlighting the variability of the disorder. Conclusion: TANGO2-related disorders can have a more diverse clinical presentation than previously anticipated. We illustrate the utility of routine ES data reanalysis whereby discovery of novel disease genes can lead to a diagnosis in previously unsolved cases and the need for additional copy-number variation analysis when ES is performed.",

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author = "Dines, {Jennifer N.} and Katie Golden-Grant and Amy LaCroix and Muir, {Alison M.} and Cintr{\'o}n, {Dianne Laboy} and Kirsty McWalter and Cho, {Megan T.} and Angela Sun and Merritt, {J. Lawrence} and Jenny Thies and Dmitriy Niyazov and Barbara Burton and Katherine Kim and Leah Fleming and Rachel Westman and Karachunski, {Peter I} and Joline Dalton and Alice Basinger and Can Ficicioglu and Ingo Helbig and Manuela Pendziwiat and Hiltrud Muhle and Helbig, {Katherine L.} and Almuth Caliebe and Ren{\'e} Santer and Kolja Becker and Sharon Suchy and Ganka Douglas and Francisca Millan and Amber Begtrup and Monaghan, {Kristin G.} and Mefford, {Heather C.}",

note = "Funding Information: We thank the families, GeneDx, and practitioners for their participation and collaboration in this case series. Research reported in this publication was supported in part by a grant from the National Institutes of Health (NS069605 to H.C.M.), and the National Institute of General Medical Sciences of the National Institutes of Health Postdoctoral Training Program in Medical Genetics (5T32GM007454 to J.N.D.). This work was also supported by intramural funds of the University of Kiel (I.H.), the German Research Foundation (HE5415/3-1 to I.H.) within the EuroEPINOMICS framework of the European Science Foundation, and individual grants by the German Research Foundation (D.F. G., HE5415/5-1, HE5415/6-1 to I.H.). Publisher Copyright: {\textcopyright} 2018, American College of Medical Genetics and Genomics.",

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AU - Dines, Jennifer N.

AU - Golden-Grant, Katie

AU - LaCroix, Amy

AU - Muir, Alison M.

AU - Cintrón, Dianne Laboy

AU - McWalter, Kirsty

AU - Cho, Megan T.

AU - Sun, Angela

AU - Merritt, J. Lawrence

AU - Thies, Jenny

AU - Niyazov, Dmitriy

AU - Burton, Barbara

AU - Kim, Katherine

AU - Fleming, Leah

AU - Westman, Rachel

AU - Karachunski, Peter I

AU - Dalton, Joline

AU - Basinger, Alice

AU - Ficicioglu, Can

AU - Helbig, Ingo

AU - Pendziwiat, Manuela

AU - Muhle, Hiltrud

AU - Helbig, Katherine L.

AU - Caliebe, Almuth

AU - Santer, René

AU - Becker, Kolja

AU - Suchy, Sharon

AU - Douglas, Ganka

AU - Millan, Francisca

AU - Begtrup, Amber

AU - Monaghan, Kristin G.

AU - Mefford, Heather C.

N1 - Funding Information: We thank the families, GeneDx, and practitioners for their participation and collaboration in this case series. Research reported in this publication was supported in part by a grant from the National Institutes of Health (NS069605 to H.C.M.), and the National Institute of General Medical Sciences of the National Institutes of Health Postdoctoral Training Program in Medical Genetics (5T32GM007454 to J.N.D.). This work was also supported by intramural funds of the University of Kiel (I.H.), the German Research Foundation (HE5415/3-1 to I.H.) within the EuroEPINOMICS framework of the European Science Foundation, and individual grants by the German Research Foundation (D.F. G., HE5415/5-1, HE5415/6-1 to I.H.). Publisher Copyright: © 2018, American College of Medical Genetics and Genomics.

PY - 2019/3/1

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N2 - Purpose: TANGO2-related disorders were first described in 2016 and prior to this publication, only 15 individuals with TANGO2-related disorder were described in the literature. Primary features include metabolic crisis with rhabdomyolysis, encephalopathy, intellectual disability, seizures, and cardiac arrhythmias. We assess whether genotype and phenotype of TANGO2-related disorder has expanded since the initial discovery and determine the efficacy of exome sequencing (ES) as a diagnostic tool for detecting variants. Methods: We present a series of 14 individuals from 11 unrelated families with complex medical and developmental histories, in whom ES or microarray identified compound heterozygous or homozygous variants in TANGO2. Results: The initial presentation of patients with TANGO2-related disorders can be variable, including primarily neurological presentations. We expand the phenotype and genotype for TANGO2, highlighting the variability of the disorder. Conclusion: TANGO2-related disorders can have a more diverse clinical presentation than previously anticipated. We illustrate the utility of routine ES data reanalysis whereby discovery of novel disease genes can lead to a diagnosis in previously unsolved cases and the need for additional copy-number variation analysis when ES is performed.

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KW - intragenic deletion

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TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants

Abstract

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Keywords

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