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| Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats |
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| Author(s): Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman JJ, Chotai K, Connarty M, Craufurd D, Curtis A, Curtis D, Davidson MJ, Differ AM, Dode C, Dodge A, Frontali M, Ranen NG, Stine OC, Sherr M, Abbott MH, Franz ML, Graham CA, Harper PS, Hedreen JC, Jackson A, Kaplan JC, Losekoot M, MacMillan JC, Morrison P, Trottier Y, Novelletto A, Simpson SA, Theilmann J, Whittaker JL, Folstein SE, Ross CA, Hayden MR |
| Source: AMERICAN JOURNAL OF HUMAN GENETICS Volume: 59 Issue: 1 Pages: 16-22 Published: JUL 1996 |
| Times Cited: 181 References: 26 |
| Abstract: Abnormal CAG expansions in the IT-15 gene are associated with Huntington disease (HD). In the diagnostic setting it is necessary to define the limits of the CAG size ranges on normal and HD-associated chromosomes. Most large analyses that defined the limits of the normal and pathological size ranges employed PCR assays, which included the CAG repeats and a CCG repeat tract that was thought to be invariant. Many of these experiments found an overlap between the normal and disease size ranges. Subsequent findings that the CCG repeats vary by 8 trinucleotide lengths suggested that the limits of the normal and disease size ranges should be reevaluated with assays that exclude the CCG polymorphism. Since patients with between 30 and 40 repeats are rare, a consortium was assembled to collect such individuals. AU 178 samples were reanalyzed in Cambridge by using assays specific for the CAG repeats. We have optimized methods for reliable sizing of CAG repeats and show cases that demonstrate the dangers of using PCR assays that include both the CAG and CCG polymorphisms. Seven HD patients had 36 repeats, which confirms that this allele is associated with disease. Individuals without apparent symptoms or signs of PID were found at 36 repeats (aged 74, 78, 79, and 87 years), 37 repeats (aged 69 years), 38 repeats (aged 69 and 90 years), and 39 repeats (aged 67, 90, and 95 years). The detailed case histories of an exceptional case from this series will be presented: a 95-year-old man with 39 repeats who did not have classical features of HD. The apparently healthy survival into old age of some individuals with 36-39 repeats suggests that the HD mutation may not always be fully penetrant. |
| Document Type: Article |
| Language: English |
| Reprint Address: Rubinsztein, DC (reprint author), ADDENBROOKES NHS TRUST, E ANGLIAN MED GENET SERV, MOL GENET LAB, HILLS RD, BOX 158, CAMBRIDGE CB2 2QQ, ENGLAND |
Addresses:
1. UNIV CAMBRIDGE, DEPT PATHOL, CAMBRIDGE CB2 1TN, ENGLAND
2. UNIV BRITISH COLUMBIA, DEPT MED GENET, VANCOUVER, BC V5Z 1M9 CANADA
3. INSERM, CNRS, INST GENET & BIOL MOL & CELLULAIRE, ILLKIRCH GRAFFENSTADEN, FRANCE
4. CHRU, STRASBOURG, FRANCE
5. UNIV LOUVAIN, CTR HUMAN GENET, LOUVAIN, BELGIUM
6. NORTHWICK PK HOSP & CLIN RES CTR, KENNEDY GALTON CTR, HARROW HA1 3UJ, MIDDX ENGLAND
7. SALISBURY DIST HOSP, WESSEX REG GENET SERV, SALISBURY, WILTS ENGLAND
8. ST MARYS HOSP, DEPT MED GENET, MANCHESTER M13 0JH, LANCS ENGLAND
9. NO GENET SERV, MOL GENET LAB, NEWCASTLE UPON TYNE, TYNE & WEAR ENGLAND
10. UNIV NEWCASTLE UPON TYNE, NEWCASTLE UPON TYNE NE1 7RU, TYNE & WEAR ENGLAND
11. GUYS HOSP, DIV MED & MOL GENET, LONDON SE1 9RT, ENGLAND
12. HOP COCHIN, BIOCHIM GENET LAB, F-75674 PARIS, FRANCE
13. TUFTS UNIV, NEW ENGLAND MED CTR, DEPT PSYCHIAT, BOSTON, MA 02111 USA
14. TUFTS UNIV, NEW ENGLAND MED CTR, DEPT PSYCHIAT & PATHOL, BOSTON, MA 02111 USA
15. BELFAST CITY HOSP, DEPT MED GENET, BELFAST BT9 7AD, ANTRIM NORTH IRELAND
16. UNIV WALES COLL MED, INST MED GENET, CARDIFF CF4 4XN, S GLAM WALES
17. JOHNS HOPKINS UNIV, DEPT NEUROSCI, BALTIMORE, MD 21218 USA
18. JOHNS HOPKINS UNIV, DEPT PSYCHIAT, BALTIMORE, MD 21218 USA
19. LEIDEN UNIV, DEPT HUMAN GENET, NL-2300 RA LEIDEN, NETHERLANDS
20. UNIV ROMA TOR VERGATA, DIPARTIMENTO BIOL, I-00173 ROME, ITALY
21. CNR, INST EXPT MED, ROME, ITALY
22. UNIV ABERDEEN, SCH MED, DEPT MED GENET, ABERDEEN AB9 2ZD, SCOTLAND
23. CTR HUMAN GENET, SHEFFIELD, S YORKSHIRE ENGLAND
24. KAROLINSKA INST, DEPT MOL MED & GERIATR MED, S-10401 STOCKHOLM, SWEDEN |
| Publisher: UNIV CHICAGO PRESS, 5720 S WOODLAWN AVE, CHICAGO, IL 60637 |
| Subject Category: Genetics & Heredity |
| IDS Number: VL455 |
| ISSN: 0002-9297 |
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