Clinical Utility of Testing

Due to the presence of unrecognized FMR1 alterations in unaffected, carrier parents, the first indication of FXS within a family is usually the diagnosis of an affected child. Unfortunately, many families do not learn the FXS diagnosis for long periods after first concerns about their child's development or behavior, and many have subsequent pregnancies before diagnosis for their first child. Such situations highlight the importance of early diagnosis so children and families can receive the benefits of genetic counseling and intervention services. Other than the infrequent deletion or point mutation, which often are spontaneous and not inherited from a parent, mothers of all FXS patients are either premutation or full-mutation carriers. In turn, at least one of the mother's parents has an FMR1 alteration. Consequently, FMR1 mutations may be present in siblings of an affected individual as well as other extended family members. It is important to remember that the daughters of unaffected males with a premutation (transmitting males) are also unaffected carriers, and that their offspring are at risk for FXS. Many families are known in which an FMR1 mutation has been transmitted through numerous generations and into family branches unknown to one another.

For developmentally delayed children, FMR1 molecular testing is diagnostic, as FXS affects development from infancy. However, the nonspecific nature of FXS during early development makes the testing approach one of ruling out FXS in most situations. The hallmark finding in almost all patients with FXS is MR, but the physical and behavioral features of males with FXS are variable prior to puberty. Physical features not readily recognizable in preschool-age boys become more obvious with age: long face, prominent forehead, large ears, prominent jaw, and enlarged testicles (macroorchidism). Motor milestones and speech are frequently delayed, and temperament often is affected (e.g., hyperactivity, hand flapping, hand biting, temper tantrums, and occasionally autism). Females with FXS usually have milder manifestations and as a result are more difficult to diagnose clinically. FXS always should be suspected in males with mild to moderate MR and females with mild MR until shown otherwise by negative FMR1 analysis.

Women who are full-mutation or premutation carriers have a 50% risk of transmitting their abnormal allele in each pregnancy. While transmission of a full mutation always leads to a child with a full mutation, the risk of a premutation transmission resulting in an affected offspring with a full mutation is proportional to the maternal premutation repeat number. Empirically, the 50% risk of a female carrier producing an affected male child is reduced to 7% if the premutation contains 56 to 59 repeats, 10% for 60 to 69 repeats, 29% for 70 to 79 repeats, 36% for 80 to 89 repeats, and 47% for 90 to 99 repeats; it reaches the maximum, 50%, when a premutation has >100 repeats. Because females have approximately 50% penetrance, the risk for producing an affected female is half that of producing an affected male in any premutation repeat interval category.

Prenatal testing for FMR1 mutations is available in many clinical molecular laboratories. Genomic DNA isolated from amniocytes obtained during amniocentesis at 16 to 18 weeks gestation or from chorionic villus sampling (CVS) at 10 to 12 weeks gestation can be used for testing. Prenatal molecular analysis proceeds in much the same fashion as that performed on DNA obtained from adult peripheral blood. However, the DNA analysis of CVS may be more complex, as chorionic villi are extraembryonic. Hyperme-thylation in CVS may be incomplete and not representative of the true FMR1 methylation status in fetal tissues. Therefore, occasionally a follow-up amniocentesis may be required to resolve ambiguous CVS test results.

General population screening for FMR1 mutations has been proposed but remains controversial. In comparison to most disorders already screened in the newborn period, FXS is more prevalent and testing is highly reliable. However, the relatively high costs and the technical complexities of testing must be resolved before population screening is possible. Protein testing of FMRP may be useful for screening populations with MR.

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