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

Abstract

Fragile X syndrome , which is caused by expanded CGG repeats of the FMR1 gene , is associated with a broad spectrum of clinical involvement and is the most common inherited form of intellectual disability. Early diagnosis and intervention are likely to lead to improved outcome for children with fragile X syndrome , but such strategies require better estimates of the frequencies of expanded alleles of the FMR1 gene. In this study , we report the results of a newborn screening study of 5267 male blood spots collected from the Northwest region of Spain as part of the national newborn screening program. The blood spots were screened using a rapid polymerase chain reaction-based method that is capable of identifying the presence of all expanded alleles for both males and females. The screened samples included 199 gray zone alleles , 21 premutation alleles , and two full mutation alleles (1 in 2633). The frequency of premutation alleles was three times higher (1 in 251) than the quoted value of 1 in 813 from a Canadian population and is fully consistent with the results of large-scale Israeli screening studies. Our results demonstrate that newborn screening for the presence of expanded FMR1 alleles is an effective means for defining the distribution of expanded FMR1 alleles in newborn populations; as such , this method is suitable for large-scale newborn screening.

Identification of Expanded Alleles of theFMR1Gene Among High-Risk Population in Indonesia by Using Blood Spot Screening

“…For DNA isolation, two disks of 3 mm in diameter were punched from the blood spot, heated with digest solution at 57°C, and processed in a Qiaxtractor (Qiagen) according to the manufacturer's protocol. The PCR amplification was performed by using primer c and f conditions as previously described (Fu et al, 1991;Fernandez-Carvajal et al, 2009). The PCR products were visualized by using the Qiaxcel genetic analyzer (Qiagen) or by capillary electrophoresis (CE) (ABI 3100; Applied Biosystems, Carlsbad, CA).…”

“…In addition, significant phenotypic involvement has emerged in some individuals with the premutation (55-200 CGG repeats), including fragile X-associated premature ovarian insufficiency (FXPOI) in females, and fragile X-associated tremor/ataxia syndrome (FXTAS) in both male and female aging carriers Sullivan et al, 2005). Prevalence for premutation alleles was *1 in 110-250 for females and 1 in 250-800 for males (Rousseau et al, 1995;Toledano-Alhadef et al, 2001;Dombrowski et al, 2002;Fernandez-Carvajal et al, 2009).…”

“…In addition, significant phenotypic involvement has emerged in some individuals with the premutation (55-200 CGG repeats), including fragile X-associated premature ovarian insufficiency (FXPOI) in females, and fragile X-associated tremor/ataxia syndrome (FXTAS) in both male and female aging carriers Sullivan et al, 2005). Prevalence for premutation alleles was *1 in 110-250 for females and 1 in 250-800 for males (Rousseau et al, 1995;Toledano-Alhadef et al, 2001;Dombrowski et al, 2002;Fernandez-Carvajal et al, 2009).The first population study of FXS performed in Indonesia, based on the screening of 176 subjects (92 males and 84 females), indicates a prevalence of 1.9% (Faradz et al, 1999). Special education needs schools, developmental disorders clinics, or health care centers are the most appropriate places for FXS screening in developing countries.…”

“…Thus, to identify individuals with FXS and FMR1-associated disorders and to provide early intervention services for children, an FMR1-sensitive and -specific screening method for both males and females is needed in countries with a large population, such as Indonesia. Tassone et al (2008) introduced a rapid, effective, and inexpensive method for screening both males and females for FMR1 allele sizes throughout the premutation and full-mutation range and is possible by using dried blood spots (Fernandez-Carvajal et al, 2009;Yuhas et al, 2009); thus, this method is suitable for large population screenings. Here, we present a high-risk screening in Central Java, Indonesia, including 176 subjects (92 males and 84 females) with ID and/or known family history of FXS.…”

Distribution of AGG interruption patterns within nine world populations

“…These samples were previously screened to determine the prevalence rates of expanded alleles. Cohorts from Australia (n = 201) (28), Chile (n = 77), the United Arab Emirates (n = 263), Guatemala (n = 151) (29), Indonesia (n = 312) (30), Italy (n = 67), Mexico (n = 277), Spain (n = 358) (31), and the United States (n = 1,359) (32) were included. Individuals were recruited from the general population for the Italy, Spain, and United States samples.…”