Analysis of a CGG sequence at the FMR-1 locus in fragile X families and in the general population

Journal Article · Wed Dec 01 04:00:00 EST 1993 · American Journal of Human Genetics; (United States)

OSTI ID:5296217

Snow, K; Doud, L K; Thibodeau, S N ^[1]; Hagerman, R ^[2]; Pergolizzi, R G; Erster, S H ^[3]

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1. Mayo Clinic and Foundation, Rochester, MN (United States)
2. Denver Children's Hospital, CO (United States)
3. North Shore University Hospital, Manhasset, NY (United States)

In this study, the authors have characterized a CGG repeat at the FMR-1 locus in more than 100 families (more than 500 individuals) presenting for fragile X testing and in 247 individuals from the general population. Both Southern blot and PCR-based assays were evaluated for their ability to detect premutations, full mutations, and variability in normal allele sizes. Among the Southern blot assays, the probes Ox1.09 or StB12.3 with a double restriction-enzyme digest were the most sensitive in detecting both small and large amplifications and, in addition, provided information on methylation of an adjacent CpG island. In the PCR-based assays, analysis of PCR products on denaturing DNA sequencing gels allowed the most accurate determination of CGG repeat number up to approximately 130 repeats. A combination of a Southern blot assay with a double digest and the PCR-sequencing-gel assay detected the spectrum of amplification-type mutations at the FMR-1 locus. In the patient population, a CGG repeat of 51 was the largest to be stably inherited, and a repeat of 57 was the smallest size of premutation to be unstably inherited. When premutations were transmitted by females, the size of repeat correlated with risk of expansion to a full mutation in the next generation. Full mutations (large repeats typically associated with an abnormal methylation pattern and mitotic instability) were associated with clinical and cytogenetic manifestations in males but not necessarily in females. In the control population, the CGG repeat changed from 13 to 61, but 94% of alleles had fewer than 40 repeats. The most frequent allele (34%) was a repeat of 30. One female had an allele (61 repeats) within a range consistent with fragile X premutations, while two other individuals each had a repeat of 52. This suggests that the frequency of unstable alleles in the general population may be [approximately]1%. 34 refs., 5 figs., 3 tabs.

• OSTI ID: 5296217
• Journal Information: American Journal of Human Genetics; (United States), Journal Name: American Journal of Human Genetics; (United States) Vol. 53:6; ISSN AJHGAG; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

550400* -- Genetics
59 BASIC BIOLOGICAL SCIENCES
CHROMOSOMES
DETECTION
DISEASES
GENE MUTATIONS
HEREDITARY DISEASES
HETEROCHROMOSOMES
HUMAN CHROMOSOMES
HUMAN X CHROMOSOME
MUTATIONS
X CHROMOSOME