Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm

Telenius, H; Kremer, Berry; Goldberg, Y P; Theilmann, Jane; Andrew, Susan E.; Zeisler, Jutta; Adam, Shelin; Greenberg, Cheryl R.; Ives, Elizabeth J.; Clarke, Lorne A.

doi:10.1038/ng0494-409

Cited by 381 publications

(313 citation statements)

References 30 publications

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“…16,17 Clinical symptoms are always found in individuals with more than 39 CAG repeats. Thus, these alleles are classified as completely penetrant.…”

Section: Discussionmentioning

confidence: 99%

Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

et al. 2012

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We studied the allelic profile of CAG and CCG repeats in 61 Brazilian individuals in 21 independent families affected by Huntington's disease (HD). Thirteen individuals had two normal alleles for HD, two had one mutable normal allele and no HD phenotype, and forty-six patients carried at least one expanded CAG repeat allele. Forty-five of these individuals had one expanded allele and one individual had one mutable normal allele (27 CAG repeats) and one expanded allele (48 CAG repeats). Eleven of these forty-five subjects had a mutant allele with reduced penetrance, and thirty-four patients had a mutant allele with complete penetrance. Inter-and intragenerational investigations of CAG repeats were also performed. We found a negative correlation between the number of CAG repeats and the age of disease onset (r ¼ À0.84; Po0.001) and no correlation between the number of CCG repeats and the age of disease onset (r ¼ 0.06). We found 40 different haplotypes and the analysis showed that (CCG) 10 was linked to a CAG normal allele in 19 haplotypes and to expanded alleles in two haplotypes. We found that (CCG) 7 was linked to expanded CAG repeats in 40 haplotypes (95.24%) and (CCG) 10 was linked to expanded CAG repeats in only two haplotypes (4.76%). Therefore, (CCG) 7 was the most common allele in HD chromosomes in this Brazilian sample. It was also observed that there was a significant association of (CCG) 7 with the expanded CAG alleles (v 2 ¼ 6.97, P ¼ 0.0084). Worldwide, the most common CCG alleles have 7 or 10 repeats. In Western Europe, (CCG) 7 is the most frequent allele, similarly to our findings.

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“…16,17 Clinical symptoms are always found in individuals with more than 39 CAG repeats. Thus, these alleles are classified as completely penetrant.…”

Section: Discussionmentioning

confidence: 99%

Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

et al. 2012

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“…Densitometric tracings were obtained from autoradiographs and the peak values recorded for cach expanded allele in blood and sperm, without overexposing the film (21). Most PCRs were repeated at least once.…”

Section: Measurement Of Densitometric Indicesmentioning

confidence: 99%

Somatic mosaicism in sperm is associated with intergenerational (CAG)_n changes in Huntington disease

Telenius

Almqvist

Kremer³

et al. 1995

Hum Mol Genet

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We have analysed the CAG repeat in the Huntington disease (HD) gene in sperm and blood from 20 unrelated HD patients. Although the CAG repeat displayed significant mosaicism in sperm from all individuals, there were marked differences in the degree of repeat instability. Individuals who had either inherited or transmitted an expanded CAG repeat displayed the highest levels of repeat mosaicism, whereas individuals who had inherited or transmitted a contracted repeat had very limited CAG mosaicism in sperm. A strong association between intergenerational change in CAG allele size and the level of sperm repeat mosaicism was determined (P = 0.019). In contrast, neither blood CAG size nor repeat mosaicism in blood, were significantly associated with intergenerational CAG changes. These data suggest the presence of a cis-acting factor, separate from CAG size, that strongly influences the intergenerational behaviour of the CAG repeat. Additional studies are needed to determine whether analysis of CAG mosaicism in sperm is useful for assessing an individual's risk for transmitting large expansions or contractions to his offspring.

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“…Mosaicism attributable to both mitotic and meiotic instability has been described in brain and sperm, and it appears to be more pronounced in juvenile-onset cases of HD associated with larger CAG expansions. 16 However, the degree of mosaicism is not significant enough to compromise the interpretation of CAG repeat lengths determined from DNA extracted from peripheral blood lymphocytes.…”

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confidence: 99%

American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, 2014 edition: technical standards and guidelines for Huntington disease

Bean

Bayrak-Toydemir

2014

Genetics in Medicine

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Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm

Cited by 381 publications

References 30 publications

Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

Somatic mosaicism in sperm is associated with intergenerational (CAG)_n changes in Huntington disease

American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, 2014 edition: technical standards and guidelines for Huntington disease

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Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm

Cited by 381 publications

References 30 publications

Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

Somatic mosaicism in sperm is associated with intergenerational (CAG)n changes in Huntington disease

American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, 2014 edition: technical standards and guidelines for Huntington disease

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Somatic mosaicism in sperm is associated with intergenerational (CAG)_n changes in Huntington disease