Prenatal diagnosis of fragile X syndrome and the risk of expansion of a premutation

Abstract

The aim of the present study was to evaluate prospectively the dynamics of the FMR1 gene. The risk of full mutation among pregnant women and the carriers, and the risk of expansion of a premutation allele to a full mutation were estimated. We identified 89 pregnant women with an expanded FMR1 gene seeking prenatal diagnosis. Amniocentesis or chorion villus sampling (CVS) was offered and a DNA test of the FMR1 gene was carried out in such pregnancies. The overall risk of full mutation among women (N = 21) with a repeat size between 60 and 80 was 4.8% (one fetus with mosaicism), and the risk of expansion of the premutation allele to a full mutation was 14% in those offspring to whom the premutation allele was transmitted. The risk of full mutation among the carriers (N = 13) with a repeat size between 81 and 100 was 61.5% (8/13), and the risk of expansion of a premutation allele to a full mutation was 89%. Only one case fell into the category of 101-200 repeats, and expansion to a full mutation was recorded. Fetuses of full mutation mothers inherited the larger allele in 64% (14/22) of the cases. The range of 40-59 repeats was safe: there were no fetal full mutations. The risk of full mutation was also low among the subjects with a repeat size between 60 and 80, whereas the risk increased significantly after 80 repeats. Maternal premutation size was positively correlated with the risk of having a full mutation offspring.

ACMG Standards and Guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics

“…In addition, they found that the premutation carriers were well distributed among all the Jewish ethnic groups, in contrast to a previous study. 39 An Italian study of ~2,000 mothers and their newborns in the general population found a premutation carrier frequency of 1 in 109 females and 1 in 225 newborn males (56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70). 48 A fragile X screen of 10,000 newborn males in Taiwan showed a prevalence of 1 in 1,674.…”

“…64 Women with alleles in this range are considered to be at risk for having affected children. [65][66][67] The smallest FMR1 premutation allele reported to expand to a full mutation in a single generation is 56 repeats. 63 Females who carry an FMR1 premutation should be offered prenatal diagnosis for all pregnancies.…”

“…67 The smallest allele known to expand to the full mutation is 56 repeats. 63 Laboratories should be familiar with publications on this topic, [65][66][67]78,96 including any current publications.…”

Screening for fragile X syndrome: a literature review and modelling study

“…Four studies reported data about the general population, 17,67,68,70 and 10 studies were about affected families. [89][90][91][92][94][95][96][97][98][99] …”

Molecular analysis of fragile X syndrome in Antalya Province

“…[2] The normal number of (CGG) n repeats is polymorphic and varies from 6 to 50. [3] When the expanded repeat numbers range from 50 to 200, the allele becomes unstable in the intergenerational transmissions and is termed as premutation. [4] The expansion of the number of repeats above a threshold of approximately 200 repeats, results in hypermetylation of the FMR1 promotor region and a lack of gene expression.…”