AssessmentsFragile X syndrome
Fragile X syndrome
USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 6-year-old adopted boy is brought to the physician to discuss his genetic testing results. The child had been having difficulties communicating with others in the classroom and was subsequently diagnosed with autism spectrum disorder and an intellectual disability. The genetic testing confirms a diagnosis of Fragile X syndrome. Which of the following family pedigrees represents this patient’s biological family history? (Arrows indicating the patient).
The “fragile” refers to the fact that under a microscope, the X chromosome looks fragile or broken at the site of the mutation.
That’s because the chromatin which makes up the chromosome gets really condensed at that point.
Fragile X is a genetic disease that affects various organ systems.
Now, the gene for Fragile X is called FMR1, which stands for Fragile X mental retardation 1.
Mental retardation is the old term for intellectual disability, which is one of the key features of Fragile X syndrome.
The FMR1 gene has a triplet repeat, or trinucleotide repeat, which means that a group of three DNA nucleotides is repeated multiple times in a row.
In FMR1, it’s the nucleotides cytosine, guanine, and guanine, or CGG.
These CGGs are found in the 5’ untranslated region of FMR1.
A 5’ untranslated region is the part of DNA at the beginning of the gene that’s made into mRNA but not protein, and helps modulate gene expression.
Just upstream from the 5’ untranslated region is FMR1‘s promoter, the region that causes the gene to be transcribed to mRNA, which is usually turned on.
Expressed FMR1 mRNA gets translated into Fragile X mental retardation protein, or FMRP, and it helps in development of the brain and other tissues.
In Fragile X syndrome, there is a repeat expansion, meaning there’s an increased number of CGG repeats in the gene.
This repeat expansion is caused by slipped mispairing, which is where the enzyme DNA polymerase gets confused when copying a repetitive sequence.
DNA polymerase loses its place among the FMR1 triplet repeats and goes back to recopy what it already just copied.
This is like getting lost in a video and watch the same part over and over.
But since DNA polymerase is making copies, the effect is an increase, or expansion, of the number of repeats.
The normal number of CGG triplets is 5-44.
Alleles with 45 to 54 CGG repeats are called intermediate expansion alleles and they don’t cause any symptoms.
Alleles with 55 to 200 CGGs are called premutation alleles, and they can cause some mild symptoms.
Finally if an allele has over 200 CGGs, then it’s considered a full fragile X syndrome mutation and can make the chromosome take on its distinctive look.
Alleles can tend to get longer and longer as DNA polymerase becomes more and more unstable copying the longer stretches of repeats, so an intermediate expansion allele can become a premutation allele, and a premutation allele can expand to become a full fragile X syndrome mutation.
The repeat expansion attracts a DNA methylase enzyme to the site and causes the cytosines in the CGG repeats to become methylated.