Instability of a premutation allele in homozygous patients with myotonic dystrophy type 1

Abbruzzese, Claudia; Porrini, Sandro Costanzi; Mariani, Bruno; Gould, Fiona K.; McAbney, John; Monckton, Darren G.; Ashizawa, Tetsuo; Giacanelli, Manlio

doi:10.1002/ana.10304

Cited by 20 publications

(17 citation statements)

References 20 publications

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“…As seen in HD, intermediate alleles of these trinucleotide disorders do not confer the disease phenotype, but due to the possibility of repeat expansion, there is a risk of disease in offspring. Furthermore, numerous factors, similar to HD, have been identified that influence the likelihood of repeat instability for these trinucleotide disorders (45,46,(68)(69)(70)(71)(72)(73). Analogous to HD, these trinucleotide disorders also lack precise quantified risk estimates for affected offspring that account for factors influencing instability.…”

Section: Discussionmentioning

confidence: 99%

Predictive testing for Huntington disease: interpretation and significance of intermediate alleles

et al. 2006

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Direct mutation analysis for Huntington disease (HD) became possible in 1993 with the identification of an expanded CAG trinucleotide repeat as the mutation underlying the disease. Expansion of CAG length beyond 35 repeats may be associated with the clinical presentation of HD. HD has never been seen in a person with a CAG size of <36 repeats. Intermediate alleles are defined as being below the affected CAG range but have the potential to expand to >35 CAG repeats within one generation. Thus, children of intermediate allele carriers have a low risk of developing HD. Currently, the intermediate allele range for HD is between 27 and 35 CAG repeats. In this study, we review the current knowledge on intermediate alleles for HD including the CAG repeat range, the intermediate allele frequency, and the clinical implications of an intermediate allele predictive test result. The factors influencing CAG repeat expansion, including the CAG size of the intermediate allele, the sex and age of the transmitting parent, the family history, and the HD gene sequence and haplotype, will also be reviewed.

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Section: Discussionmentioning

confidence: 99%

Predictive testing for Huntington disease: interpretation and significance of intermediate alleles

et al. 2006

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“…All reports concerning the correlation between CTG- repeat and disease severity were based on the analysis of CTG repeats expansion in each patient's leukocyte rather than in cardiomyocytes. We should focus on CTG repeats in cardiomyocytes when we make an attempt to investigate about the correlation between cardiac involvement and the CTG repeats expansion, as it was recently reported that somatic instability is often seen in patients of DM1 (22,23).…”

Section: Discussionmentioning

confidence: 99%

Re-entry Circuit in Ventricular Tachycardia Due to Focal Fatty-fibrosis in a Patient with Myotonic Dystrophy

Muraoka¹,

Negoro²,

Terasaki

et al. 2005

Intern. Med.

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“…The DM1 predisposing mutation seems to have originated only once for both the disease-causing alleles and the protomutated state were found to be in tight association with the same set of surrounding markers, suggesting a single common ancestral chromosome (Abbruzzese et al 2002;Brunner et al 1989;Goldman et al 1995Goldman et al , 1996Junghans et al 2001;Yamaoka et al 1990). Due to its single origin, the ancestral haplotype represents a genetic signature of DM1 or its protomutated alleles.…”

Section: Introductionmentioning

confidence: 99%

Anatomy of a founder effect: myotonic dystrophy in Northeastern Quebec

et al. 2005

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Founder effects are largely responsible for changes in frequency profiles of genetic variants in local populations or isolates. They are often recognized by elevated incidence of certain hereditary disorders as observed in regions of Charlevoix and Saguenay-Lac-Saint-Jean (SLSJ) in Northeastern Quebec. Dominantly transmitted myotonic dystrophy (DM1) is highly prevalent in SLSJ where its carrier rate reaches 1/550, compared with 1/5,000 to 1/50,000 elsewhere. To shed light on the origin of DM1 in this region, we have screened 50 nuclear DM1 families from SLSJ and studied the genetic variation in a 2.05 Mb (2.9 cM) segment spanning the site of the expansion mutation. The markers analyzed included 22 biallelic SNPs and two microsatellites. Among 50 independent DM1 chromosomes, we distinguished ten DM1-associated haplotypes and grouped them into three haplotype families, A, B and C, based on the relevant extent of allele sharing between them. To test whether the data were consistent with a single entry of the mutation into SLSJ, we evaluated the age of the founder effect from the proportion of recombinant haplotypes. Taking the prevalent haplotype A1_21 (58%) as ancestral to all the disease-associated haplotypes in this study, the estimated age of the founder effect was 19 generations, long predating the colonization of Nouvelle-France. In contrast, considering A1_21 as ancestral to the haplotype family A only, yielded the estimated founder age of nine generations, consistent with the settlement of Charlevoix at the turn of 17th century and subsequent colonization of SLSJ. We conclude that it was the carrier of haplotype A (present day carrier rate of 1/730) that was a "driver" of the founder effect, while minor haplotypes B and C, with corresponding carrier rates of 1/3,000 and 1/10,000, respectively, contribute DM1 to the incidence level known in other populations. Other studies confirm that this might be a general scenario in which a major "driver" mutation/haplotype issued from a founder effect is found accompanied by distinct minor mutations/haplotypes occurring at background population frequencies.

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Instability of a premutation allele in homozygous patients with myotonic dystrophy type 1

Cited by 20 publications

References 20 publications

Predictive testing for Huntington disease: interpretation and significance of intermediate alleles

Predictive testing for Huntington disease: interpretation and significance of intermediate alleles

Re-entry Circuit in Ventricular Tachycardia Due to Focal Fatty-fibrosis in a Patient with Myotonic Dystrophy

Anatomy of a founder effect: myotonic dystrophy in Northeastern Quebec

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