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.
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.
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Authors: R H Myers; J Leavitt; L A Farrer; J Jagadeesh; H McFarlane; C A Mastromauro; R J Mark; J F Gusella Journal: Am J Hum Genet Date: 1989-10 Impact factor: 11.025
Authors: F Laccone; U Engel; E Holinski-Feder; M Weigell-Weber; K Marczinek; D Nolte; D J Morris-Rosendahl; C Zühlke; K Fuchs; H Weirich-Schwaiger; G Schlüter; G von Beust; A M Vieira-Saecker; B H Weber; O Riess Journal: Neurology Date: 1999-09-11 Impact factor: 9.910
Authors: S E Andrew; Y P Goldberg; B Kremer; H Telenius; J Theilmann; S Adam; E Starr; F Squitieri; B Lin; M A Kalchman Journal: Nat Genet Date: 1993-08 Impact factor: 38.330
Authors: M Duyao; C Ambrose; R Myers; A Novelletto; F Persichetti; M Frontali; S Folstein; C Ross; M Franz; M Abbott Journal: Nat Genet Date: 1993-08 Impact factor: 38.330
Authors: Jian-Liang Li; Michael R Hayden; Elisabeth W Almqvist; Ryan R Brinkman; Alexandra Durr; Catherine Dodé; Patrick J Morrison; Oksana Suchowersky; Christopher A Ross; Russell L Margolis; Adam Rosenblatt; Estrella Gómez-Tortosa; David Mayo Cabrero; Andrea Novelletto; Marina Frontali; Martha Nance; Ronald J A Trent; Elizabeth McCusker; Randi Jones; Jane S Paulsen; Madeline Harrison; Andrea Zanko; Ruth K Abramson; Ana L Russ; Beth Knowlton; Luc Djoussé; Jayalakshmi S Mysore; Suzanne Tariot; Michael F Gusella; Vanessa C Wheeler; Larry D Atwood; L Adrienne Cupples; Marie Saint-Hilaire; Jang-Ho J Cha; Steven M Hersch; Walter J Koroshetz; James F Gusella; Marcy E MacDonald; Richard H Myers Journal: Am J Hum Genet Date: 2003-08-01 Impact factor: 11.025
Authors: Ji-Hyun Lee; Jong-Min Lee; Eliana Marisa Ramos; Tammy Gillis; Jayalakshmi S Mysore; Shotaro Kishikawa; Tiffany Hadzi; Audrey E Hendricks; Michael R Hayden; Patrick J Morrison; Martha Nance; Christopher A Ross; Russell L Margolis; Ferdinando Squitieri; Cinzia Gellera; Estrella Gomez-Tortosa; Carmen Ayuso; Oksana Suchowersky; Ronald J Trent; Elizabeth McCusker; Andrea Novelletto; Marina Frontali; Randi Jones; Tetsuo Ashizawa; Samuel Frank; Marie-Helene Saint-Hilaire; Steven M Hersch; Herminia D Rosas; Diane Lucente; Madaline B Harrison; Andrea Zanko; Ruth K Abramson; Karen Marder; Jorge Sequeiros; G Bernhard Landwehrmeyer; Ira Shoulson; Richard H Myers; Marcy E MacDonald; James F Gusella Journal: Biochem Biophys Res Commun Date: 2012-07-03 Impact factor: 3.575