• Many clinicians focus on the clinical features associated with fragile X. These features are usually subtle, may even be absent or may not become apparent until adolescence. While the presence of mental disabilities is consistent in males, shyness and autistic behaviors may or may not be present. Hypotonia and associated joint laxity are nonspecific findings as are recurrent ear infections or seizures. Testicular enlargement is evident only in post-adolescent males.

• Family history is often negative in children diagnosed with fragile X syndrome and is helpful only when positive for maternally inherited mental retardation. Family history is generally more useful when deciding whether or not to test a female with mild learning problems.

• All males with unexplained, significant developmental delay should be screened for fragile X as well as any other chromosomal variation. Boys are often identified by significant speech delay with or without ADHD. For males selected in this way about 1 in 20-25 will be positive. The pick-up rate is higher for males with obvious clinical and behavioral features or with a suggestive family history. In this same group about 1 in 30-50 boys will have a detectable chromosome variation (deletion, duplication, marker or sex chromosome variation).

• Selected females should also be screened both for fragile X and chromosome abnormalities. While about one third of females with a fully expanded fragile X gene are of normal intelligence, one third have learning disabilities and one third are mildly retarded. If there is a suggestive family history, any girl with learning disabilities should clearly be tested for fragile X. Any woman with a known family member with fragile X who is at risk for inheriting the gene should be offered screening. A girl with learning disabilities associated with short stature, dysmorphic features and/or minor or major birth defects should be screened for chromosomal abnormalities before testing for fragile X.

• No one should have cytogenetic testing for fragile X in 1998! The optimal way to diagnose fragile X is by molecular technologies (preferably using both PCR and southern blot analyses). Testing is usually done on blood collected in purple top EDTA tubes whereas cytogenetic studies are done on blood drawn in a green top Na heparin tube. Therefore, to do both analyses one should ideally obtain blood in two 5cc purple top and one 5-10cc green top tubes.

• The region just adjacent to (upstream of) the fragile X gene or FMR1 gene has a series of CGG triplet repeats with the normal number ranging from 29-40 repeats. Individuals with more than 60 repeats are considered to have an unstable or premutation size region that is susceptible to even greater expansion during meiosis. If one thinks of meiosis as a Xeroxing process, a premutation may lead to reduplication of the CGG region which, for unknown reasons, occurs exclusively in egg cells. Normal males may carry a premutation size region but usually pass it on unchanged to their normal daughters who are subsequently at risk for having affected sons.

• Fragile X syndrome occurs when the triplet repeats exceed 200 resulting in methylation or switching off of the FMR1 gene. If you no longer make this gene product you are affected with fragile X. Females who have two X chromosomes are able to make some of the FMR1 gene product and this is why they are less often or more mildly affected.

• Although some laboratories are using only a single methodology, interpretation of the molecular test results is an art and frequently requires having both PCR and southern blot results for optimal diagnostic accuracy. This is especially true for females who may be carriers or have a full gene expansion. We have encountered numerous instances where a misdiagnosis has been made using only on methodology.

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