ClinVar Genomic variation as it relates to human health

Kremer et al. (1991) demonstrated that the presence of an unstable expanded trinucleotide repeat sequence, designated p(CCG)n, in the 5-prime untranslated region of the FMR1 gene is the basis of fragile X syndrome (FXS; 300624). The authors showed that normal X chromosomes have about 40 +/- 25 copies of p(CCG)n and that within these limits the sequence is a stable DNA polymorphism. The fragile X genotype was characterized by an increased amount of unstable DNA that maps to the repeat. The mutation causing fragile X syndrome contains over 200 CCG repeats (Devys et al., 1992). Premutations A premutation in the FMR1 gene is defined as an expansion of approximately 55 to 200 CGG repeats. Hagerman et al. (2001) reported 5 men with an FMR1 premutation, ranging from 78 to 98 repeats, who presented in the sixth decade with progressive intention tremor, parkinsonism, cognitive decline, generalized atrophy on MRI, and impotence (FXTAS; 300623). Levels of FMR1 mRNA were 2 to 4 times higher than normal, which the authors suggested resulted in a pathogenic gain-of-function effect. Murray et al. (1998) screened 147 women with idiopathic premature ovarian failure (POF1; 311360) and found a significant association with premutations in the FMR1 gene, with 6 women having premutations, including 4 familial and 2 sporadic cases, but no women with full mutations in the FMR1 gene. In an international collaborative study of 760 women from fragile X families, Allingham-Hawkins et al. (1999) found that 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. In 63 (16%) of the premutation carriers, menopause occurred before the age of 40, compared with none of the full-mutation carriers and 1 (0.4%) of the controls, indicating a significant association between premature menopause and premutation carrier status. (less)

Kremer et al. (1991) demonstrated that the presence of an unstable expanded trinucleotide repeat sequence, designated p(CCG)n, in the 5-prime untranslated region of the FMR1 gene is the basis of fragile X syndrome (FXS; 300624). The authors showed that normal X chromosomes have about 40 +/- 25 copies of p(CCG)n and that within these limits the sequence is a stable DNA polymorphism. The fragile X genotype was characterized by an increased amount of unstable DNA that maps to the repeat. The mutation causing fragile X syndrome contains over 200 CCG repeats (Devys et al., 1992). Premutations A premutation in the FMR1 gene is defined as an expansion of approximately 55 to 200 CGG repeats. Hagerman et al. (2001) reported 5 men with an FMR1 premutation, ranging from 78 to 98 repeats, who presented in the sixth decade with progressive intention tremor, parkinsonism, cognitive decline, generalized atrophy on MRI, and impotence (FXTAS; 300623). Levels of FMR1 mRNA were 2 to 4 times higher than normal, which the authors suggested resulted in a pathogenic gain-of-function effect. Murray et al. (1998) screened 147 women with idiopathic premature ovarian failure (POF1; 311360) and found a significant association with premutations in the FMR1 gene, with 6 women having premutations, including 4 familial and 2 sporadic cases, but no women with full mutations in the FMR1 gene. In an international collaborative study of 760 women from fragile X families, Allingham-Hawkins et al. (1999) found that 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. In 63 (16%) of the premutation carriers, menopause occurred before the age of 40, compared with none of the full-mutation carriers and 1 (0.4%) of the controls, indicating a significant association between premature menopause and premutation carrier status. (less)

Kremer et al. (1991) demonstrated that the presence of an unstable expanded trinucleotide repeat sequence, designated p(CCG)n, in the 5-prime untranslated region of the FMR1 gene is the basis of fragile X syndrome (FXS; 300624). The authors showed that normal X chromosomes have about 40 +/- 25 copies of p(CCG)n and that within these limits the sequence is a stable DNA polymorphism. The fragile X genotype was characterized by an increased amount of unstable DNA that maps to the repeat. The mutation causing fragile X syndrome contains over 200 CCG repeats (Devys et al., 1992). Premutations A premutation in the FMR1 gene is defined as an expansion of approximately 55 to 200 CGG repeats. Hagerman et al. (2001) reported 5 men with an FMR1 premutation, ranging from 78 to 98 repeats, who presented in the sixth decade with progressive intention tremor, parkinsonism, cognitive decline, generalized atrophy on MRI, and impotence (FXTAS; 300623). Levels of FMR1 mRNA were 2 to 4 times higher than normal, which the authors suggested resulted in a pathogenic gain-of-function effect. Murray et al. (1998) screened 147 women with idiopathic premature ovarian failure (POF1; 311360) and found a significant association with premutations in the FMR1 gene, with 6 women having premutations, including 4 familial and 2 sporadic cases, but no women with full mutations in the FMR1 gene. In an international collaborative study of 760 women from fragile X families, Allingham-Hawkins et al. (1999) found that 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. In 63 (16%) of the premutation carriers, menopause occurred before the age of 40, compared with none of the full-mutation carriers and 1 (0.4%) of the controls, indicating a significant association between premature menopause and premutation carrier status. (less)