Clinical Review


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Genetic medicine is fast gaining recognition as an essential component of clinical care. Since this Update last year, 2 areas have seen notable progress:

  • New guidelines were issued for fragile X screening in women of reproductive age, and
  • Research on free fetal DNA in the maternal circulation deepened our understanding of its diagnostic potential. Clinical applications are emerging in both avenues, and there will be further investigation and refinement. Be sure to check this column again next year!

New guidelines on who to test for mental retardation marker

Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005;7:584–587.

McConkie-Rosell A, Finucane B, Cronister A, Abrams L, Bennett RL, Petterson BJ. Genetic counseling for fragile X syndrome: updated recommendations of the National Society of Genetic Counselors. J Genet Couns. 2005;14:249–270.

Fragile X syndrome is the most common inherited cause of mental retardation. The condition can occur in both males and females and is characterized by a range of behavioral changes consistent with autism spectrum, mental retardation, and developmental delay, as well as a facial phenotype that tends to become more recognizable as the individual ages.

Test is not for everybody

New guidelines issued by the American College of Medical Genetics recommended general population screening only within the constructs of research protocols. In selected populations, however, screening should be considered (TABLE 1). Among preconception and prenatal patients, directed interrogation of the family history for findings suggestive of fragile X syndrome can be guided by these recommendations.

Prevalence. ObGyns should be aware of the increasing spectrum of full and premutation fragile X phenotypes and the relatively high prevalence of premutations among women.

Anatomy of fragile X

Changes in a specific region of the X chromosome known as the fragile X mental retardation-1 (FMR-1) gene are responsible for the syndrome. Elongation of an unstable CGG repeat sequence at the 5′ end of FMR-1 leads to hypermethylation, impaired translation, and altered production of the fragile X mental retardation protein. Investigations of knock-out mice reveal that this protein plays an important role in prenatal and postnatal brain development, especially in the area of dendrite maturation.

Among Caucasians, the characteristic features of fragile X syndrome occur in approximately 1 in 4,000 males and 1 in 8,000 females and are associated with elongation of the FMR-1 gene to more than 200 CGG repeats (a full mutation). Initial studies of other races suggest a similar range of full mutations in males and females.


Fragile X syndrome: Diagnostic and carrier testing guidelines

Both women and men with
  • mental retardation
  • or developmental delay
  • or autism…especially with:
    Physical or behavioral characteristics of fragile X
    or family history of fragile X
    or a relative with undiagnosed mental retardation
Persons seeking reproductive counseling who have
  • family history of fragile X syndrome
  • or a relative with undiagnosed mental retardation
Fetuses of carrier mothers
Affected individuals or relatives in whom the diagnosis was made by cytogenetic studies
Women with elevated follicle-stimulating hormone, especially with family history of
  • premature ovarian failure
  • or fragile X syndrome
  • or relative of either sex with undiagnosed mental retardation
Men or women with late-onset intention tremor or ataxia…especially with family history of
  • movement disorders
  • or fragile X
  • or undiagnosed mental retardation
Source: Sherman et al.

Which offspring will inherit the gene?

In the general population, the FMR-1 region has variable lengths.1 In most individuals, 40 or fewer CGG repeats are present and the region remains stable when passed from either parent to the child. Occasionally, however, individuals inherit expansions of this repeat region—either slight (41–60 repeats, intermediate range) or larger (61–200, premutation range). Repeats in the premutation range are carried by 1 in 700 to 1,000 males and 1 in 113 to 350 females.

Expansion of the premutation to a full FMR-1 mutation depends on the sex of the transmitting parent, the length of repeats, and the frequency of AGG interspersion. Only the first 2 criteria are available for clinical interpretation. FMR-1 expansion occurs only in the X originating from the maternal cell line. The larger the premutation, the more likely it will expand to a full mutation (TABLE 2).

Timing of the maternal FMR-1 expansion can vary, with meiotic, postzygotic, and mitotic instability of CGG length all reported.


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