Fragile-X Carrier Screening and the Prevalence of Premutation and Full-Mutation Carriers in Israel

Abstract

Fragile-X syndrome is caused by an unstable CGG trinucleotide repeat in the FMR1 gene at Xq27. Intermediate alleles (51-200 repeats) can undergo expansion to the full mutation on transmission from mother to offspring. To evaluate the effectiveness of a fragile-X carrier-screening program, we tested 14,334 Israeli women of child-bearing age for fragile-X carrier status between 1992 and 2000. These women were either preconceptional or pregnant and had no family history of mental retardation. All those found to be carriers of premutation or full-mutation alleles were offered genetic counseling and also prenatal diagnosis, if applicable. We identified 207 carriers of an allele with >50 repeats, representing a prevalence of 1:69. There were 127 carriers with >54 repeats, representing a prevalence of 1:113. Three asymptomatic women carried the fully mutated allele. Among the premutation and full-mutation carriers, 177 prenatal diagnoses were performed. Expansion occurred in 30 fetuses, 5 of which had an expansion to the full mutation. On the basis of these results, the expected number of avoided patients born to women identified as carriers, the cost of the test in this study (U.S. $100), and the cost of lifetime care for a mentally retarded person (>$350,000), screening was calculated to be cost-effective. Because of the high prevalence of fragile-X premutation or full-mutation alleles, even in the general population, and because of the cost-effectiveness of the program, we recommend that screening to identify female carriers should be carried out on a wide scale.

Screening for Expanded Alleles of the FMR1 Gene in Blood Spots from Newborn Males in a Spanish Population

“…Such projections tend to underestimate the disease prevalence, and hence allele frequencies, since individuals with only mild or no apparent learning difficulties would be excluded. Interestingly, a recent report 8 that used an average of the known frequency for premutation females (1/126) 3,7 to estimate the expected frequencies of full mutation and (male) premutation alleles yielded frequencies of 1/2355 (males and females) for full mutation alleles and 1/282 for premutation alleles (male); remarkably close to the observations of the current study.…”

“…1 However, there remains some uncertainty regarding the premutation allele frequencies 1,[3][4][5][6][7] due in part to lingering issues of ascertainment bias, 8 but also to real frequency differences across ethnic and regional populations. For example, in the screens of males and females in Eastern Canada, allele frequencies were estimated to be ϳ1/800 males and ϳ1/260 females.…”

Wild-Type Male Offspring of fmr-1+/− Mothers Exhibit Characteristics of the Fragile X Phenotype

“…Although most fragile X individuals inherit a premutated allele that undergoes triplet expansion resulting in a full mutation, some inherit a fully mutated allele from H carrier mothers. Males with the full mutation always have some degree of mental retardation while H females with a full mutation are not, or are only moderately affected (Toledano-Alhadef et al, 2001). Besides mental retardation, fragile X individuals can have seizures, attention deficit, hyperactivity, anxiety, and symptoms associated with autism (Chen and Toth, 2001;Consortium, 1994 Here we report that in the mouse model of fragile X hyperactivity is maternally transmitted, at least partly, while seizures, reduced startle and increased prepulse inhibition are strictly Mendelian traits.…”

Carrier screening in preconception consultation in primary care

“…Carrier frequency may be different again in other population groups, with no carriers found in 370 women screened in a Japanese study (Otsuka et al 2010) and 1,002 women from Taiwan (Huang et al 2003), although these were much smaller sample sizes. The feasibility, cost-effectiveness and cost-benefit of populationbased carrier screening for FXS have been widely discussed, with arguments generally in favour (Wildhagen et al 1998;Toledano-Alhadef et al 2001;Song et al 2003;Palomaki 1994;Finucane 1996;Meadows and Sherman 1996;Musci 2005). However, guidelines from the American College of Medical Geneticists state that population carrier screening for FXS is not recommended except within well-defined clinical research protocols ) because of the difficulties around counselling and education regarding the meaning and interpretation of results (McConkie-Rosell et al 2005).…”

“…The majority were with pregnant women (Berkenstadt et al 2007;Cronister et al 2005;Fanos et al 2006;Huang et al 2003;Pesso et al 2000;Spence et al 1996;Ryynanen et al 1999;Toledano-Alhadef et al 2001;Kallinen et al 2001), while some included relatively smaller numbers of nonpregnant women (Pesso et al 2000;Spence et al 1996;Toledano-Alhadef et al 2001;Berkenstadt et al 2007;Geva et al 2000). Most studies essentially focused on the uptake of testing, with rates varying between 7.9% ) and 21% (Spence et al 1996) in the USA, 80% in Israel (Pesso et al 2000), and 85% (Ryynanen et al 1999) and 92% respectively in two Finnish studies (Kallinen et al 2001).…”