Direct diagnosis by DNA analysis of the fragile X syndrome was studied in 511 persons from 63 families with the syndrome at the Institute National de la Sante et de la Recherce Medicale (INSERM), Unite 184, Faculte de Medecine, Strasbourg, France and other laboratories. Analysis of EcoRI and Eagl digests of DNA distinguished between the normal genotype, the permutation and the full mutation. The method was more reliable than cytogenetic testing. All 103 males and 31 of 59 females with full mutations had mental retardation. All mothers of affected children were carriers of either a permutation or a full mutation. Direct diagnosis by DNA analysis is an efficient primary test for the identification of fragile X syndrome after birth and prenatally. [1]

COMMENT. The authors propose that direct DNA diagnosis may be helpful in the differential diagnosis of mental retardation and in the genetic counseling of families with the fragile X syndrome. The use of a single EcoRI digestion to test for a fragile X mutation in boys or girls with unexplained mental retardation, late onset of speech, or autistic or hyperactive behavior is proposed even if there is no family history of mental retardation. The disease is caused by mutations that increase the size of a specific DNA fragment of the X chromosome. Affected persons have both a full mutation and abnormal DNA methylation. Persons with a smaller increase in the size of this DNA fragment (a permutation) have little or no risk of retardation but are at high risk of having affected children or grandchildren. Among persons with a full mutation, 100% of males and 50% of females will be mentally impaired, whereas the risk of retardation is about 3% in carriers of a permutation. The role of cytogenetic analysis in diagnosis must now be reevaluated.

The prenatal diagnosis of fragile X syndrome by direct detection of the unstable DNA sequence using Southern Blot Analysis is reported from The Department of Cytogenetics and Molecular Genetics, Adelaide Children’s Hospital and Queen Victoria Hospital, Adelaide, Australia [2]. The carrier status of a cytogenetically normal woman in a family with the fragile X syndrome and the mutation in her male fetus were detected by analysis of a cordocentesis sample and led to the termination of the pregnancy.

Shapiro L from New York Medical College, Valhalla, NY, in an editorial, comments that cytogenetic analysis of fragile X syndrome may be relegated to a secondary role but should be used for index cases to verify that the typical fragile X mutation is present in the family before DNA analyses are performed and genetic counseling undertaken. [3]