engleski

Genetic screening for the fragile X syndrome in population at risk: clinical preselection notably improves cost-effectiveness of fragile X population studies

Fragile X syndrome is the most common inherited form of mental retardation currently known. Its frequency and serious consequences for affected individuals and their families clearly emphasise the need to establish concerted programs that would systematically screen populations at risk to identify affected individuals and to pursue screening of their families. The aim of this study was to evaluate the need for a fragile X screening program in a clinically preselected pediatric population in our country. The study included: a) preselection of at risk children who were mentally retarded and had at lest one physical and/or behavioural characteristic related to the fragile X phenotype, b) fragile X DNA analysis using Expand Long PCR and Southern blot techniques, c) genetic counselling of fragile X families, d) further testing of relatives of any newly identified cases, and e) retrospective clinical analysis identifying the most effective selection criteria for future studies. The studied population included 108 clinically preselected children who attended Children's Hospital Zagreb between November 1995 and December 1997. If the child was positive for fragile X mutation, the parents were offered testing of their carrier status or of any other at risk family member. Medical records of the 81 boys and 27 girls were retrospectively reviewed for six physical and behavioural characteristics that best describe fragile X phenotype. These included mental retardation, positive family history, behavioural disturbances, large or prominent ears, elongated face, and macrocephaly. Each characteristic was scored as two if definitely present, one if borderline, slightly or somewhat present and zero if absent or not mentioned. The maximum possible score was 12. After DNA results were obtained, total scores were correlated with fragile X positive and negative findings. For fragile X diagnosis we performed two-stage DNA screening combining Expand Long PCR and southern blot analysis. In the group of 108 unrelated children (81 boys an 27 girls), 14 fragile X positive cases were detected (17.3% of males, 0% of females and 13% overall). The high rate of fragile X positive individuals suggested the efficacy of simple clinical examination as a method of preselection. The parents of 14 affected children were offered genetic counselling and further DNA testing. Nine of 14 parents requested further testing (64.3%), and 6 premutation and 3 full mutation female carriers were identified. By retrospective clinical analysis scoring criteria based on a simplified six-item fragile X checklist were evaluated. We estimated that a score of 5 and above out of the maximum of 12 would eliminate approximately 70% of testing leading to the negative result, without missing any affected males. Our preliminary results also indicate the underdiagnosing of the fragile X syndrome in our population suggesting the need for a larger comprehensive genetic epidemiologic study of at risk populations in Croatia. We believe that clinical preselection combined with DNA testing represents the most cost-effective diagnostic approach to this challenging task.

Fragile X syndrome; clinical preselection

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