Suggestive findings of FMR1 disorder and diagnosis
Received: 01-Dec-2021 Accepted Date: Dec 14, 2021; Published: 21-Dec-2021
Citation: Gunapalli KK. Suggestive findings of FMR1 disorder and diagnosis. J Clin Gen Genomics 2021;4(4): 5.
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FMR1 disorders should be considered in individuals with following clinical and associated findings:
Fragile X syndrome
Males and females with intellectual disability or developmental delay was unknown cause. Males with mysterious autism spectrum ailment and females with unexplained autism spectrum ailment and the presence of an additional indicator: phenotype compatible with FXS, family history of Xlinked neurodevelopmental ailments, or premature ovarian failure, ataxia, or tremors in near relations.
Diagnosis of an FMR1 disorder is established through use of specialized molecular genetic testing. It should be noted that typical multigene panels and comprehensive genomic are useful only when no CGG repeat expansion is detected but FXS is still suspected. FMR1 relevant disorders are caused by CGG tri nucleotide repeat expansion in 5' UTR of FMR1 with abnormal gene methylation for most alleles with more than 200 repeats. Normally, a definite diagnosis of FXS needs presence of a full-mutation repeat size while diagnosis of FXTAS or FXPOI is related with a permutation sized repeat.
FMR1 alleles are categorized according to number of 5' UTR CGG tri nucleotide repeats and methylation status of repeat region. However, distinction between allele groups is not absolute and must be made by considering both family history and repeat instability. Size boundary between intermediate and pre mutation groups listed below is not precise and caution is guided. For a summary of types of FMR1 alleles and clinical status of individuals with expanded alleles. Stability of alleles of fewer than 90 repeats are deeply influenced by number of AGG interspersions within CGG repeat sequence, both with respect to risk for size change in intermediate alleles and small pre mutations and expansion to a full mutation in pre mutation alleles are more than about 60 repeats. This information should be used when suitable for counseling families about expansion risk. See anticipation for full information on factors such as AGGs that effect FMR1 CGG repeat stability. Alleles of this size have little meiotic or mitotic instability and are typically transmitted without any increase or decrease in repeat number. Though, some instability in normal repeats has been reported, with alleles that contain no AGG interspersions having a greater likelihood to be unstable. Population distribution of FMR1 repeat alleles shows highest percentage of individuals with approximately 29-31 repeats, smaller but significant percentages cluster around 20 and 40 repeats.
Intermediate alleles do not cause FXS. But, about 14% of intermediate alleles are unstable and may expand into pre mutation range when transmitted by mother. They are not known to increase to full mutations; therefore, offsprings are not at increased threat for FXS. Historically, largest repeat included in intermediate range has been 54, use of 54 as upper limit for normal alleles is a conservative estimate reflecting observations that transmission of alleles with 54 or fewer repeats from mothers to their offspring has not resulted in an affected individual to date. Conservative nature of estimate also reflects potential imprecision in laboratory measurement of repeat number during diagnostic testing, however, to date no transmission of alleles with 55 or fewer repeats is known to have resulted in an affected individual.
Clinical laboratories performing FMR1 analysis typically state their estimated precision range when measuring intermediate alleles and usually report their estimates as repeats. Thus, it may be prudent to consider reported test results with 55 repeats as potential pre mutations. If the repeat precision estimate is not on the laboratory report, the laboratory should be contacted in order to regulate if a result should be considered as a potential pre mutation. Alleles of this size are not linked with FXS but do convey increased risk for FXTAS and FXPOI. Because of potential repeat instability upon transmission of pre mutation alleles, women with alleles in this range are measured to be at risk of having children with FXS, although this risk is heavily dependent on the number of AGG interspersions for minor pre mutation alleles.