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The Report: Reports include results, interpretation and often recommendations. The style of reports ranges from brief to detailed with explanations and relevant educational information. It is helpful if physicians send copies of the report to their patients. Never hesitate to call a laboratory to inquire about the meaning of a result or a statement in a report. Seeking the assistance of a genetic counselor is highly recommended for patients and their families. Results Results typically include the following: Presence or absence of the mutation, the mutation category (premutation, full mutation, both (mosaic), or 'grey zone'), and the CGG repeat number. The methylation status of full mutations may also be included. CGG repeat number: The CGG repeat number should always be given for a mutation and is sometimes also given when it is in the normal range. CGG repeat number differences in the normal range have no clinical significance. Males with a normal FMR1 gene or a premutation have one CGG repeat number (one gene) and most females have two because the FMR1 gene is on the X chromosome. Some females without a mutation have the same CGG repeat number for both alleles. The most common CGG repeat number in the general population is 29 or 30. Slight variation in the exact repeat number determined for a particular person is expected between labs or between repeated tests by the same lab. Small differences are not clinically relevant and do not affect the interpretation of the result. For full mutations, specific CGG repeat number(s) are sometimes given or the report may state the mutation has >200 repeats. Once a full mutation is over 200 repeats and methylated, the magnitude of the repeat number does not appear to significantly influence clinical outcome. In other words, a full mutation of 800 CGG repeats, for example, would not be expected to have more severe clinical consequences than a full mutation of 300 repeats. For any given individual with a full mutation, there is often more than one CGG repeat number. This reflects the presence of different sized mutations in different populations of blood cells. In most cases, full mutations have one to three sizes, but some people have many more. Different sizes are thought to result from varying degrees of CGG repeat number increase in different cells when the mother's premutation expands to a full mutation during development of the embryo. Methylation status: Methylation is a biological process by which extra molecules ('CH3') attach to gene control areas (promoters) and turn off gene function. Normal FMR1 genes and ones containing a premutation are unmethylated and functional, leading to normal production of the FMR1 protein, FMRP. FMR1 genes with full mutations are usually methylated (turned off) and therefore cannot produce FMRP. The lack of FMRP causes fragile X syndrome. In most cases, full mutations are methylated in all cells tested and methylation is referred to as 'complete'. However, in rare cases the full mutations in a fraction of cells miss being methylated and so methylation is considered 'incomplete' or 'partial'. The methylation status (complete or incomplete) of full mutations is sometimes noted in reports. Research has shown that in some cases the degree of methylation can influence the severity of fragile X symptoms (McConkie-Rosell et al.,1993). Specifically, if methylation is present in less than 10% of cells tested in males with a full mutation, intellectual impairment tends to be milder than in males with complete methylation of the full mutation (Taylor et al., 1994). Interpretation Standard interpretations are (i) No mutation: Rules out diagnosis of fragile X syndrome or carrier status (Note: in very rare cases, fragile X syndrome has been found to be caused by deletion of part or all of the fragile X gene or by a point mutation) ii) Premutation: Establishes that the person tested is a carrier of fragile X syndrome, (iii) Full mutation: Establishes the diagnosis of fragile X syndrome in males and in females with clinical signs of the disorder and establishes carrier status in females. A few unusual results and interpretations are discussed below. The grey zone: The most important point about an FMR1 gene with CGG repeat number in the 'grey zone' (between approximately 40 and 55 repeats), is that it cannot be the cause of clinical problems. The gene is perfectly functional. Cognitive impairment in an individual with an FMR1 gene of this size must stem from another source. The only risk associated with a gene of CGG repeat number in the grey zone is that it may be unstable from generation to generation and could eventually expand to a full mutation. Therefore, there is a slight risk of fragile X syndrome in distant descendants. The risk for instability of a gene with less than 50 repeats is quite small. Mosaicism: When referring to fragile X syndrome, the term 'mosaic' means the presence in one individual of both a full mutation and a premutation in the cells tested. This definition should not be confused with the term 'somatic mosaic' which is sometimes seen in reference to the presence of more than one size of full mutation. At least fifteen percent of males and approximately six percent of females with fragile X syndrome are mosaic for the full mutation and premutation. This mosaicism is thought to be established during embryogenesis when a mother's premutation expands to a full mutation in some but not all cells. It is believed that in female fragile X carriers the mutation in the oocytes is a premutation, even if a full mutation is present in the rest of the body. Although it is theoretically possible that presence of the premutation (which produces some FMRP) in the mosaic males could improve clinical outcome, most of these individuals are affected to a similar degree as males with only a full mutation. A study in collaboration with Dr. Randi Hagerman to determine whether levels of FMRP in male mosaics correlate with clinical severity is currently in progress in our laboratory. For more details on mosaicism in fragile X syndrome, see Nolin and Brown, 1996. Incomplete methylation of a full mutation: This observation is discussed in the 'methylation status' section above. Incomplete methylation can have prognostic significance in certain cases. Recommendations Reports may include recommendations for fragile X DNA testing of relatives, for other testing if fragile X is ruled out, and for genetic counseling to be offered to the extended family. Annette K. Taylor, M.S., Ph.D. |
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