Excerpted from Chapter 5 of Genetics and Mental Retardation Syndromes: A New Look at Behavior and Interventions, by Elisabeth M. Dykens, Ph.D., Robert M. Hodapp, Ph.D., & Brenda M. Finucane, M.S.

Copyright © 2000 by Paul H. Brookes Publishing Co. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.

Diagnosis

Until 1991, when the exact genetic mutation underlying fragile X syndrome was first identified, the diagnosis was made by visualizing the fragile X chromosome in cytogenetic preparations. This technique was highly accurate for diagnosing affected males, and could also identify more than 90% of fragile X females with mental retardation. Fragile X chromosome testing could not, however, detect most unaffected female and male carriers, nor could it be used reliably for prenatal diagnosis.

In 1991, the gene responsible for fragile X syndrome was discovered (Verkerk et al., 1991). Dubbed with the acronym FMR1 (fragile X mental retardation 1), the gene in its normal state produces a protein product thought to play a key role in both pre- and postnatal brain development. The FMR1 gene contains a repetitive sequence of the trinucleotide CGG, which in most people is repeated anywhere from 6 to 50 times. Most intellectually typical fragile X carriers have an expanded FMR1 gene sequence, ranging from 50 to 200 CGG repeats in size. Repeat sizes within this range are called fragile X premutations and do not appear to affect the production of FMR1 protein.

Male and female premutation carriers show no outward signs of fragile X syndrome; their cognitive or behavior functioning is not affected (Mazzocco & Holden, 1996; Reiss, Freund, Abrams, Boehm, & Kazazian, 1993). Individuals who carry the premutation, however, can pass the mutation to their children. In females, fragile X premutations are unstable and can expand further when passed down to the next generation. If the CGG sequence expands to larger than 200 repeats in size it is called a full mutation. An FMR1 gene with a full mutation becomes inactive, or methylated, and does not make its protein product, resulting in symptoms of fragile X syndrome. Virtually all males with a methylated full mutation show clinical characteristics of fragile X syndrome. More than half of females with a full mutation have fragile X symptoms, the others being protected from symptoms by the normal FMR1 gene on their second X chromosome.

Direct deoxyribonucleic acid (DNA) testing of the FMR1 gene has now replaced the earlier chromosome test in most instances. The testing can distinguish among normal, premutation, and full mutation size gene sequences, meaning that unaffected male and female family members can find out whether they are fragile X carriers. DNA studies can also tell the extent to which the FMR1 gene is inactivated, which is sometimes helpful for determining a child’s prognosis. DNA for fragile X testing is usually extracted from blood samples, or from fetal cells in amniotic fluid or other tissues for prenatal diagnosis.

Hereditary Implications for Families

Because of the existence of both pre- and full mutations, as well as the sex chromosomal differences among males and females, fragile X syndrome has a particularly complex inheritance pattern. Carrier females can pass their fragile X mutation to children of either sex. Carrier males can only transmit the fragile X mutation to their daughters, never to their sons; as in all X-linked disorders, there is no male-to-male inheritance. The fragile X premutation does not expand in size when passed from an unaffected father to his daughters, and they too are unaffected. As females though, they are at risk for having children with an expanded full mutation. Whenever one person in a family is found to have fragile X syndrome, the gene mutation can almost always be traced back to previous generations, even though many of the gene carriers in a family may be unaffected.

For example, a boy with fragile X syndrome may be the only person in his family with significant mental retardation. Because of its inheritance pattern, however, we know that he received the fragile X from his mother, who must have inherited either a pre- or full mutation from one of her parents. Although unaffected, the boy’s mother is at high risk for having other children with fragile X syndrome. Likewise, the mother’s siblings and cousins could also be carriers. The boy’s unaffected sister has a strong chance of carrying a fragile X pre- or full mutation, which might then result in fragile X syndrome in her future children. The boy’s unaffected brother could carry a fragile X premutation, which all of his daughters would inherit, putting his future grandchildren at high risk for having fragile X syndrome. This common condition clearly has far-reaching genetic implications for the extended family, once again illustrating the importance of identifying the diagnosis in people with mental retardation and other developmental disabilities.

Prevalence

The fragile X chromosome test did not become widely available until the mid-1980s, and until then, few researchers anticipated the high prevalence of the syndrome or its wide-ranging effects in both males and females. Although initial prevalence estimates have recently been revised downward, fragile X syndrome continues to rank as the most common known inherited cause of mental retardation, occurring in 1 in 4,000 males and at least half as many females (Turner, Webb, Wake, & Robinson, 1996). Furthermore, as many as 1 in 259 women in the general population may be a fragile X premutation carrier and at risk for having affected children (Rousseau, Rouillard, Morel, Khandjian, & Morgan, 1995). Fragile X syndrome appears in all racial and ethnic groups and has been found to account for up to 14% of unexplained mental retardation in males. Approximately one third of all X-linked mental retardation is due to fragile X syndrome.