THE FRAGILE-X-SYNDROME IS STILL UNDERDIAG NOSED - EFFICACY OF MOLECULAR TESTING IN MENTALLY-RETARDED PROBANDS

Background. - The fragile X mental retardation syndrome is the most co mmon cause of inherited mental retardation. Identification of the unst able mutation responsible for the disease has allowed the design of a fully reliable molecular test for the diagnosis of the disease and for genetic counselling (identification of clinically normal carriers and prenatal diagnosis). We started in July 1991 to search for the mutati on in mentally retarded probands, with no known cause for their phenot ype. We present the results of a 42-month experience. Population and m ethods. - One thousand and one hundred fourty-nine probands were analy sed. In case of a positive diagnosis, an extension of the molecular st udy to relatives was proposed. DNA samples were studied by Southern bl ot following EcoRI or EcoRI + EagI digestion. Clinical data were colle cted from referring clinicians. Results. - Seventy-three carriers of a full mutation were identified, belonging to 52 families. The mean age of the fragile X probands was 16 +/- 14 years, which is very surprisi ng for a disease that causes significant manifestations by the age of 2 to 3 years. This indicates an insufficient knowledge about this dise ase in France. Most of the demands for the test were from clinical gen eticists. This diagnosis is of major importance for genetic counsellin g, as illustrated by the following study of 108 women at risk in these families. Conclusions. - The importance of an early diagnosis followe d by an extended family study, for carrier screening and prevention of this severe disease, justifies molecular testing on any child with me ntal retardation or significant language delay of unknown cause, in th e absence of clinical signs formally excluding a fragile X diagnosis.