Fragile X syndrome

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Fragile X syndrome

Genetics

Genetic disorders

Achondroplasia
Alagille syndrome (NORD)
Familial adenomatous polyposis
Familial hypercholesterolemia
Hereditary spherocytosis
Huntington disease
Li-Fraumeni syndrome
Marfan syndrome
Multiple endocrine neoplasia
Myotonic dystrophy
Neurofibromatosis
Polycystic kidney disease
Treacher Collins syndrome
Tuberous sclerosis
von Hippel-Lindau disease
Albinism
Alpha-thalassemia
Beta-thalassemia
Cystic fibrosis
Friedreich ataxia
Gaucher disease (NORD)
Glycogen storage disease type I
Glycogen storage disease type II (NORD)
Glycogen storage disease type III
Glycogen storage disease type IV
Glycogen storage disease type V
Hemochromatosis
Krabbe disease
Leukodystrophy
Mucopolysaccharide storage disease type 1 (Hurler syndrome) (NORD)
Niemann-Pick disease type C
Niemann-Pick disease types A and B (NORD)
Phenylketonuria (NORD)
Polycystic kidney disease
Primary ciliary dyskinesia
Sickle cell disease (NORD)
Tay-Sachs disease (NORD)
Wilson disease
Cri du chat syndrome
Williams syndrome
Angelman syndrome
Prader-Willi syndrome
Beckwith-Wiedemann syndrome
Mitochondrial myopathy
Klinefelter syndrome
Turner syndrome
Fragile X syndrome
Friedreich ataxia
Huntington disease
Myotonic dystrophy
Down syndrome (Trisomy 21)
Edwards syndrome (Trisomy 18)
Patau syndrome (Trisomy 13)
Alport syndrome
Fragile X syndrome
Fabry disease (NORD)
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Hemophilia
Lesch-Nyhan syndrome
Mucopolysaccharide storage disease type 2 (Hunter syndrome) (NORD)
Muscular dystrophy
Ornithine transcarbamylase deficiency
Wiskott-Aldrich syndrome
X-linked agammaglobulinemia
Autosomal trisomies: Pathology review
Miscellaneous genetic disorders: Pathology review
Muscular dystrophies and mitochondrial myopathies: Pathology review

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High Yield Notes

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Fragile X syndrome

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Questions

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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).  

External References

First Aid

2024

2023

2022

2021

Autism spectrum disorder p. 574

fragile X syndrome p. 60

Fragile X syndrome p. 60

chromosome association p. 62

dominant, inheritance of p. 57

Mitral valve prolapse p. 296

fragile X syndrome p. 60

Transcript

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With Fragile X syndrome, sometimes just called Fragile X, the “X” refers to the X chromosome, where the disease gene is located.

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.