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Dr. Rajendran Rajendran
Dr. RAJENDRAN’S INSTITUTE OF MEDICAL EDUCATION

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JIPMER 2015

8) A 32-year-old female is 8 weeks pregnant. Both the husband and wife are carriers of fragile X syndrome. She had conceived after a long period of infertility and multiple treatment regimens. She is very desirous to continue with the pregnancy, but she is very much bothered about the outcome of the pregnancy. What is the most appropriate advice?

a. Carrier testing of the parents

b. Termination of pregnancy

c. Amniocentesis in 2nd trimester

d. MRI


Ans- (c)

Fragile X syndrome

Fragile X syndrome, also termed Martin-Bell syndrome or marker X syndrome, is the most common cause of inherited mental retardation, intellectual disability, and autism. It is the second most common cause of genetically associated mental deficiencies, after trisomy 21.

Fragile X syndrome is inherited in an X-linked dominant pattern. The genetic defect is dynamic and lies at the distal end of the long arm of the X chromosome. Mutations in the FMR1 gene cause fragile X syndrome. The FMR1 gene provides instructions for making a protein called FMRP. A mutation in a DNA segment known as the CGG triplet repeat causes fragile X syndrome. Normally, this DNA segment is repeated from 5 to about 40 times. In people with fragile X syndrome, however, the CGG segment is repeated more than 200 times. The abnormally expanded CGG segment inactivates (silences) the FMR1 gene, which prevents the gene from producing a protein called fragile X mental retardation protein. Loss of this protein leads to the signs and symptoms of fragile X syndrome. Both boys and girls can be affected, but because boys have only one X chromosome, a single fragile X is likely to affect them more severely.

X-linked dominant means that in females (who have two X chromosomes), a mutation in one of the two copies of a gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of a gene in each cell causes the disorder.

There are four allelic forms of the gene: Normal, intermediate, premutation and affected. Individuals with 45-54 repeats are unaffected, but they risk passing a premutation on to future generations. A span of 55-199 repeats is known as a premutation, whereas 200 or more repeats is a full mutation.

The “FMR1 DNA Test” (“Fragile X DNA Test”) is the “standard of care” for determining the presence of Fragile X. DNA testing detects more than 99 percent of individuals (both males and females). The FMR1 DNA Test can be administered with PCR or the Southern blot analysis in a blood sample. This test can be used for prenatal diagnosis in both amniotic fluid cells and chorionic villus samples. The number of repeats is directly proportional to the risk of the disorder in an offspring.

Prenatal diagnosis can be accomplished by amniocentesis or CVS. Specimens obtained by either can be used to accurately determine the CGG repeat number. A female with the fragile X premutation is at risk to have offspring with the full mutation. The risk of a full mutation in an offspring is 5 percent or less if the CGG repeat number is below 70 but exceeds 95 percent with 100 to 200 CGG repeats. Expansion is extremely unlikely in a male premutation carrier, but all of his daughters will carry the premutation.

? Fragile X Syndrome and Related Conditions
o Clinical Genomics: Practical Applications in Adult Patient Care, Chapter 159

? Genetics > Fragile X Syndrome
o Williams Obstetrics, 24e, Chapter 13

? Genetics & Dysmorphology > 3. (X-Linked) Fragile X Syndrome
o CURRENT Diagnosis & Treatment: Pediatrics, 22e, Chapter 37
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