2025 – PAGE 259 – GENETICS & INHERITED DISEASES
FRAGILE X SYNDROME
Fragile X syndrome is caused by a mutation in the FMR1 gene, causing CGG trinucleotide repeats with genetic anticipation (severity increases in successive generations). Over 200 repeats cause the full condition, while 40-200 repeats result in a premutation. Findings include intellectual disability, delayed milestones, social awkwardness, a long face with a prominent jaw, large ears, and macroorchidism (oversized testicles).
PEARLS: This is the most common inherited cause of intellectual disability. The most common cause of intellectual disability is Down’s. Though both boys and girls carry the defective gene, it tends to be less symptomatic in females. So look for a MALE patient on the pediatric exam. Assume females don’t express it because the bad X becomes inactivated.
IMAGE: www.pbrlinks.com/FRAGILEX1
MNEMONIC: (and mnemonic image) Note the X’s below. The top makes a large V to remind you of the LONG face and CHIN. The smaller X’s represent LARGE EARS. Note how they are fairly large compared to the rest of the face. You could also imagine that they represent X-shaped earrings. Lastly, the OO represent macroorchidism. Big testicle & prominent jaw—pick Fragile X and move on!
X-LINKED RECESSIVE DISORDERS
PEARLS
- Any female who inherits an X chromosome with an X-linked recessive disorder should be a CARRIER, and should NOT BE AFFECTED. Whether or not this is true is up for debate, but it’s a good rule of thumb for the exam. Just assume that there is always X-inactivation and it becomes a Barr body.
- If the mom is a carrier and the dad is unaffected, there is a 50% chance of a SON being affected and a 50% chance of a daughter being a carrier. Work it out:
| X | Y | |
| Xr | XrX (carrier female) | XrY (affected male) |
| X | XX (normal female) | XY (normal male) |
In the rare case where the father is affected and the mother is a carrier, half the boys and half the girls will be affected (XrY and XrXr).
MNEMONIC: If you squint your eyes, an X can look like a man’s tuXedo. If you don’t like the mnemonics below, make your own by attaching a tuX to a related story.