Hello,
This week’s topic is on Fragile X syndrome.
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-Daniel
Questions
Question 47
A 32-year-old woman presents to the clinic for genetic counseling. She is a known premutation carrier of Fragile X syndrome (170 and 30 CGG repeats in the FMR1 gene). Due to her premutation carrier status, she is at increased risk for developing which of the following during her lifetime?
Question 48
The patient in question 47 is contemplating having children. Which of the following molecular features in the mother would protect against a CGG repeat expansion in her fetus?
Question 49
What is the molecular mechanism that underlies Fragile X syndrome?
Explanation
Answers:
Q47: All of the above
Q48: C→A variant in CGG repeat
Q49: Transcriptional silencing of FMR1
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. FXS is caused by a trinucleotide repeat expansion (TRE) in the FMR1 gene, which is located on the X chromosome. Fragile X syndrome affects both boys and girls, although boys are generally more severely affected due to their single X chromosome. Management of FXS in children is mainly supportive, though there are also gene therapies in development for FXS. Women who are Fragile X premutation carriers, such as the patient in question 47, are at risk for having children with FXS and for developing complications including tremors, ataxia, early menopause, and psychiatric disorders (discussed further below).
Genetic anticipation
Trinucleotide repeat disorders like Fragile X Syndrome often exhibit genetic anticipation, whereby the number of trinucleotide repeats increases in successive generations, leading to more severe symptoms and earlier onset of the disease. Anticipation in FMR1 occurs more frequently when the trinucleotide repeat expansion is inherited from the mother, as there is a higher chance of repeat expansion during oogenesis than during spermatogenesis. Anticipation has been observed in several other genetic disorders caused by trinucleotide repeat expansions, such as myotonic dystrophy and Huntington's disease. Mechanistically, the trinucleotide repeat sequences cause slippage of the DNA polymerase and subsequent expansion of the repeat during DNA replication.
Interspersed AGG repeats
The presence of the interspersed AGG repeats (Question 48) in the CGG repeat region has been shown to reduce the risk of repeat expansion in subsequent generations and therefore the risk of a premutation carrier having a child with Fragile X syndrome. This protective effect of AGG interspersions is thought to occur through the stabilization of the repeat region, thereby reducing the likelihood of slippage during DNA replication. Furthermore, the total number of AGG interruptions within the maternal CGG repeat tract is inversely correlated with the risk of TRE (i.e. more AGG interruptions lower the risk of TRE even further).
Molecular genetics and diagnosis of Fragile X syndrome
Fragile X syndrome is caused by a CGG trinucleotide repeat expansion in the FMR1 gene. The syndrome is diagnosed based on the presence of a full mutation repeat size (>200 CGG repeats) and subsequent hypermethylation of FMR1, which results in transcriptional silencing (Question 49) of the affected FMR1 allele. PCR (polymerase chain reaction) followed by capillary electrophoresis is the most common technique used for the molecular diagnosis of FXS. PCR amplifies the CGG repeat region within the FMR1 gene, and capillary electrophoresis quantifies the number of CGG repeats at single nucleotide resolution. This approach allows classification of individuals as normal, premutation carriers, or full mutation carriers (see table below).
💡Note: Trinucleotide repeat length for FMR1 is not part of most exomes or genomes and must be ordered as a separate test!
Fragile X premutation carriers (55-200 CGG repeats)
Individuals who are heterozygous for a Fragile X premutation are at increased risk of developing three conditions (Question 47):
Fragile X-associated tremor/ataxia syndrome (FXTAS): As the name suggests, patients with FXTAS present with intention tremor, cerebellar gait ataxia, and Parkinson-like symptoms. FXTAS is present in ~ 40% of males >50 years old and in 20% of females with a FMR1 premutation.
Fragile X-associated primary ovarian insufficiency (FXPOI): Female premutations carriers may develop early menopause, also known as primary ovarian insufficiency (POI), that occurs before age 40 years. It is present in 20% of women with the premutation and is associated with an increased risk of osteoporosis and cardiovascular disease as long-term sequelae from the lack of estrogen.
Fragile X-associated neuropsychiatric disorders (FXAND): This is a broad term that encompasses a range of behavioral, cognitive, and emotional problems that may occur in individuals with a FMR1 premutation. These can include anxiety, depression, attention-deficit/hyperactivity disorder (ADHD), and other psychiatric disorders. FXAND can affect both males and females with a premutation, and the severity and presentation can vary widely between individuals.
Historical note: Origin of the term “Fragile X”
Learning objective
Fragile X Syndrome is an inherited trinucleotide repeat disorder that causes intellectual disability and autism. The syndrome affects both boys and girls, but boys are generally more severely affected due to their single X chromosome. Women who are premutation carriers are at risk of POI, FXTAS, neuropsychiatric disorders, and of having children with FXS. The presence of AGG interruptions within the maternal FMR1 CGG repeat region reduces the risk of having a child with FXS. FMR1 trinucleotide repeat testing is currently not part of most genomes or exomes and must be ordered as a separate test.
2023 ABMGG General Exam Blueprint | V. Single Gene Inheritance → c. Atypical inheritance → iv. Dynamic mutations: trinucleotide repeat expansions (page 3)
Additional Resources
FMR1 Disorders. https://www.ncbi.nlm.nih.gov/books/NBK1384/
Fragile X Syndrome - causes, symptoms, diagnosis, treatment, pathology (Osmosis)