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CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion

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CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. / Lee, J-M; Ramos, E M; Lee, J-H; Gillis, T; Mysore, J S; Hayden, M R; Warby, S C; Morrison, P; Nance, M; Ross, C A; Margolis, R L; Squitieri, F; Orobello, S; Di Donato, S; Gomez-Tortosa, E; Ayuso, C; Suchowersky, O; Trent, R J A; McCusker, E; Novelletto, A; Frontali, M; Jones, R; Ashizawa, T; Frank, S; Saint-Hilaire, M H; Hersch, S M; Rosas, H D; Lucente, D; Harrison, M B; Zanko, A; Abramson, R K; Marder, K; Sequeiros, J; Paulsen, J S; Landwehrmeyer, G B; Myers, R H; MacDonald, M E; Gusella, J F; PREDICT-HD study of the Huntington Study Group (HSG).

In: NEUROLOGY, Vol. 78, No. 10, 06.03.2012, p. 690-5.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Lee, J-M, Ramos, EM, Lee, J-H, Gillis, T, Mysore, JS, Hayden, MR, Warby, SC, Morrison, P, Nance, M, Ross, CA, Margolis, RL, Squitieri, F, Orobello, S, Di Donato, S, Gomez-Tortosa, E, Ayuso, C, Suchowersky, O, Trent, RJA, McCusker, E, Novelletto, A, Frontali, M, Jones, R, Ashizawa, T, Frank, S, Saint-Hilaire, MH, Hersch, SM, Rosas, HD, Lucente, D, Harrison, MB, Zanko, A, Abramson, RK, Marder, K, Sequeiros, J, Paulsen, JS, Landwehrmeyer, GB, Myers, RH, MacDonald, ME, Gusella, JF & PREDICT-HD study of the Huntington Study Group (HSG) 2012, 'CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion', NEUROLOGY, vol. 78, no. 10, pp. 690-5. https://doi.org/10.1212/WNL.0b013e318249f683

APA

Lee, J-M., Ramos, E. M., Lee, J-H., Gillis, T., Mysore, J. S., Hayden, M. R., Warby, S. C., Morrison, P., Nance, M., Ross, C. A., Margolis, R. L., Squitieri, F., Orobello, S., Di Donato, S., Gomez-Tortosa, E., Ayuso, C., Suchowersky, O., Trent, R. J. A., McCusker, E., ... PREDICT-HD study of the Huntington Study Group (HSG) (2012). CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. NEUROLOGY, 78(10), 690-5. https://doi.org/10.1212/WNL.0b013e318249f683

Vancouver

Lee J-M, Ramos EM, Lee J-H, Gillis T, Mysore JS, Hayden MR et al. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. NEUROLOGY. 2012 Mar 6;78(10):690-5. https://doi.org/10.1212/WNL.0b013e318249f683

Bibtex

@article{763bad3db7124a4e9fbf06047bb92d9c,
title = "CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion",
abstract = "OBJECTIVE: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.METHODS: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.RESULTS: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.CONCLUSIONS: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.",
keywords = "Adult, Age of Onset, Alleles, Female, Genotype, Humans, Huntington Disease, Male, Trinucleotide Repeat Expansion, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",
author = "J-M Lee and Ramos, {E M} and J-H Lee and T Gillis and Mysore, {J S} and Hayden, {M R} and Warby, {S C} and P Morrison and M Nance and Ross, {C A} and Margolis, {R L} and F Squitieri and S Orobello and {Di Donato}, S and E Gomez-Tortosa and C Ayuso and O Suchowersky and Trent, {R J A} and E McCusker and A Novelletto and M Frontali and R Jones and T Ashizawa and S Frank and Saint-Hilaire, {M H} and Hersch, {S M} and Rosas, {H D} and D Lucente and Harrison, {M B} and A Zanko and Abramson, {R K} and K Marder and J Sequeiros and Paulsen, {J S} and Landwehrmeyer, {G B} and Myers, {R H} and MacDonald, {M E} and Gusella, {J F} and {PREDICT-HD study of the Huntington Study Group (HSG)}",
year = "2012",
month = mar,
day = "6",
doi = "10.1212/WNL.0b013e318249f683",
language = "English",
volume = "78",
pages = "690--5",
journal = "NEUROLOGY",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

RIS

TY - JOUR

T1 - CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion

AU - Lee, J-M

AU - Ramos, E M

AU - Lee, J-H

AU - Gillis, T

AU - Mysore, J S

AU - Hayden, M R

AU - Warby, S C

AU - Morrison, P

AU - Nance, M

AU - Ross, C A

AU - Margolis, R L

AU - Squitieri, F

AU - Orobello, S

AU - Di Donato, S

AU - Gomez-Tortosa, E

AU - Ayuso, C

AU - Suchowersky, O

AU - Trent, R J A

AU - McCusker, E

AU - Novelletto, A

AU - Frontali, M

AU - Jones, R

AU - Ashizawa, T

AU - Frank, S

AU - Saint-Hilaire, M H

AU - Hersch, S M

AU - Rosas, H D

AU - Lucente, D

AU - Harrison, M B

AU - Zanko, A

AU - Abramson, R K

AU - Marder, K

AU - Sequeiros, J

AU - Paulsen, J S

AU - Landwehrmeyer, G B

AU - Myers, R H

AU - MacDonald, M E

AU - Gusella, J F

AU - PREDICT-HD study of the Huntington Study Group (HSG)

PY - 2012/3/6

Y1 - 2012/3/6

N2 - OBJECTIVE: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.METHODS: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.RESULTS: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.CONCLUSIONS: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.

AB - OBJECTIVE: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.METHODS: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.RESULTS: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.CONCLUSIONS: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.

KW - Adult

KW - Age of Onset

KW - Alleles

KW - Female

KW - Genotype

KW - Humans

KW - Huntington Disease

KW - Male

KW - Trinucleotide Repeat Expansion

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1212/WNL.0b013e318249f683

DO - 10.1212/WNL.0b013e318249f683

M3 - SCORING: Journal article

C2 - 22323755

VL - 78

SP - 690

EP - 695

JO - NEUROLOGY

JF - NEUROLOGY

SN - 0028-3878

IS - 10

ER -