Assessment of a clinical checklist in the diagnosis of fragile X syndrome in India

Abstract

Fragile X syndrome (FRAXA) is one of the most common forms of mental retardation. It is caused by the expansion of cytosine-guanine-guanine (CGG) repeats in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene, located at Xq27.3. The number of CGG repeats in the FMR1 gene occurs in four distinct ranges: 2-50 (normal), 50-60 (gray zone), 60-200 (premutation), and > 200 (full mutation). When the number of CGG repeats exceeds 200, the gene becomes hypermethylated and transcriptionally silenced, which results in the loss of FMR protein and causes FRAXA. The key clinical features of FRAXA are mental retardation, macro-orchidism, long face, prominent jaw, connective tissue abnormalities, and behavioral problems. A modified 15-item checklist was used to assess the clinical features in 337 individuals (316 males and 21 females) who have mental retardation of unknown etiology. These patients were in institutions. Molecular diagnosis was performed using polymerase chain reaction and Southern blot analysis and revealed that 14 males were positive for FRAXA. Studies of the families of the affected males revealed an additional 11 affected males and 20 carrier females. Retrospective analysis of clinical features was performed in a total of 327 males and 41 females. Six clinical features were statistically significant in FRAXA individuals when compared to non-FRAXA individuals. These features were hyperactivity (p < 0.05), poor eye contact (p < 0.001), hyper extensibility of joints (p < 0.001), large ears (p < 0.001), macro-orchidism (p < 0.001), and a family history of mental retardation (p < 0.001). When a total score of 5 out of 15 was used as the threshold clinical score, 73.18% of the patients with total scores < 5 could be eliminated as FRAXA-negative patients, thereby improving the reliability of FRAXA testing using the clinical checklist.