AGG interruptions and maternal age affect FMR1 CGG repeat allele stability during transmission

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• 作者：Carolyn M Yrigollen (4)
  Loreto Martorell (5)
  Blythe Durbin-Johnson (6)
  Montserrat Naudo (5)
  Jordi Genoves (5)
  Alessandra Murgia (7)
  Roberta Polli (7)
  Lili Zhou (8)
  Deborah Barbouth (9)
  Abigail Rupchock (9)
  Brenda Finucane (10)
  Gary J Latham (11)
  Andrew Hadd (11)
  Elizabeth Berry-Kravis (8)
  Flora Tassone (12) (4)
  
  4. Department of Biochemistry and Molecular Medicine ; University of California ; Davis ; School of Medicine ; 2700 Stockton Blvd. ; Suite 2102 ; Sacramento ; CA ; 95817 ; USA
  5. Molecular Genetics Section ; Hospital Sant Joan de D茅u ; Barcelona ; Spain
  6. Department of Public Health Sciences ; University of California ; Davis ; Davis ; CA ; USA
  7. Laboratory of Molecular Genetics of Neurodevelopment ; Department of Women鈥檚 and Children鈥檚 Health ; University of Padova ; Padova ; Italy
  8. Department of Pediatrics ; Neurological Sciences ; and Biochemistry ; Rush University Medical Center ; Chicago ; IL ; USA
  9. Dr. John T. Macdonald Foundation ; Department of Human Genetics ; Miller School of Medicine ; University of Miami ; Miami ; FL ; USA
  10. Geisinger Autism and Developmental Medicine Institute ; Lewisburg ; PA ; USA
  11. Asuragen ; Inc. ; Austin ; TX ; USA
  12. MIND Institute ; University of California ; Davis ; School of Medicine ; Davis ; CA ; USA
  
• 关键词：AGG interruptions ; premutation ; FMR1 ; gray/intermediate allele ; full mutation ; risk of expansion
• 刊名：Journal of Neurodevelopmental Disorders
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：6
• 期：1
• 全文大小：1,053 KB
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  10. Yrigollen, CM, Durbin-Johnson, B, Gane, L, Nelson, DL, Hagerman, R, Hagerman, PJ, Tassone, F (2012) AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome. Genet Med 14: pp. 729-736 CrossRef
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• 刊物主题：Neurosciences; Neurobiology; Neuropsychology; Psychiatry; Human Genetics; Pediatrics;
• 出版者：BioMed Central
• ISSN：1866-1955

文摘

Background The presence of AGG interruptions in the CGG repeat locus of the fragile X mental retardation 1 (FMR1) gene decreases the instability of the allele during transmission from parent to child, and decreases the risk of expansion of a premutation allele to a full mutation allele (the predominant cause of fragile X syndrome) during maternal transmission. Methods To strengthen recent findings on the utility of AGG interruptions in predicting instability or expansion to a full mutation of FMR1 CGG repeat alleles, we assessed the outcomes of 108 intermediate (also named gray zone) and 710 premutation alleles that were transmitted from parent to child, and collected from four international clinical sites. We have used the results to revise our initial model that predicted the risk of a maternal premutation allele expanding to a full mutation during transmission and to test the effect of AGG interruptions on the magnitude of expanded allele instability of intermediate or premutation alleles that did not expand to a full mutation. Results Consistent with previous studies, the number of AGG triplets that interrupts the CGG repeat locus was found to influence the risk of allele instability, including expansion to a full mutation. The total length of the CGG repeat allele remains the best predictor of instability or expansion to a full mutation, but the number of AGG interruptions and, to a much lesser degree, maternal age are also factors when considering the risk of transmission of the premutation allele to a full mutation. Conclusions Our findings demonstrate that a model with total CGG length, number of AGG interruptions, and maternal age is recommended for calculating the risk of expansion to a full mutation during maternal transmission. Taken together, the results of this study provide relevant information for the genetic counseling of female premutation carriers, and improve the current predictive models which calculate risk of expansion to a full mutation using only total CGG repeat length.