Genetic Defect That Causes Fragile X Disorder Is Widespread

Fragile X syndrome (FXS), the most common single gene cause of inherited intellectual disabilities and autism, is characterized by a cytosine-guanine-guanine (CGG)-repeat expansion in the portion of the first exon of the fragile X mental retardation 1 gene (FMR1).

Scientists at the University of California (Davis, CA; USA) conducted blood spot screening of 14,207 newborns with 7,312 males and 6,895 females, in three birthing hospitals across the United States of America beginning in November 2008, using a polymerase chain reaction (PCR)-based approach. Genomic DNA isolated from the blood samples was amplified using Fast Start PCR protocol (Roche Diagnostics, Indianapolis, IN, USA).

The investigators examined the prevalence of expanded alleles of FMR1 gene. Defects in FMR1 cause conditions as diverse as fragile X syndrome, and a Parkinson's disease-like condition called fragile X-associated tremor/ataxia syndrome, or FXTAS. The term "fragile X" is used because of the altered appearance of the X chromosome among sufferers from the conditions. The screening method utilized allowed for precise quantification of CGG allele size, distribution of allele sizes within different ethnic groups and determination of the prevalence of gray zone and premutation alleles in both males and females.

The degree of disability from defects in FMR1 depends upon the number of repetitions of the sequence of the proteins cytosine-guanine-guanine (CGG) in the promoter region of the gene. The range of repeats in normal individuals is between six and 40. CGG repeats greater than 200 cause what is called the full mutation and fragile X syndrome. Fewer repeats, in the range of 55 to 200, result in a variation called a premutation. The study suggests that the prevalence of the premutation in both males and females is higher than was found in a previous large study in North America. In addition, this study provides the expected approximately 2:1 ratio of female to male carriers.

Flora Tassone, PhD, the senior author said, "This study shows that newborn screening for the FMR1 mutation is technically possible on a large scale. However, the screening will identify far more carrier and gray-zone infants than those with a full fragile X mutation. As we now know that there may be clinical involvement with these individuals, such as FXTAS, we need to better understand the impact of identifying these mutations on families before widespread newborn screening can be instituted." The study was published online on December 21, 2012, in the journal Genome Medicine.

Related Links:
University of California Davis
Roche Diagnostics