USMLE Guide: Genetics of Fragile X Syndrome

Introduction

Fragile X Syndrome (FXS) is a genetic disorder characterized by intellectual disability, behavioral and learning challenges, and various physical characteristics. This USMLE guide will provide essential information about the genetics of Fragile X Syndrome, including its inheritance pattern, molecular basis, and diagnostic approaches.

1. Inheritance Pattern

FXS follows an X-linked dominant inheritance pattern. This means that the gene mutation responsible for FXS is located on the X chromosome and can be inherited from either the mother or the father. However, the severity of the disease and the risk of transmission differ between males and females due to X chromosome inactivation.

• Males: Male individuals have one X chromosome and one Y chromosome. If the X chromosome they inherit from their mother carries the FXS mutation, they will develop the disorder. Males are generally more severely affected by FXS than females due to the lack of a second X chromosome to compensate for the mutated gene.
• Females: Females have two X chromosomes. If one X chromosome carries the mutation, they are considered carriers. However, the presence of a normal X chromosome can often compensate for the mutated gene, resulting in milder symptoms or even being asymptomatic.

2. Molecular Basis

FXS is caused by an expansion of the CGG trinucleotide repeat within the FMR1 gene located on the X chromosome. In unaffected individuals, the CGG repeat region typically consists of 5 to 40 repeats. However, in individuals with FXS, the CGG repeat expands to over 200 repeats.

• Normal Range: 5-40 CGG repeats
• Premutation Range: 55-200 CGG repeats
• Full Mutation Range: Over 200 CGG repeats

The presence of a full mutation leads to methylation of the FMR1 gene, resulting in its inactivation and subsequent absence of the Fragile X Mental Retardation Protein (FMRP). Lack of FMRP disrupts normal brain development and functioning, leading to the symptoms observed in FXS.

3. Clinical Presentation

The clinical presentation of FXS can vary widely, but some common features include:

• Intellectual disability: Ranging from mild to severe, intellectual disability is a hallmark of FXS.
• Behavioral challenges: Individuals with FXS may exhibit hyperactivity, attention deficit, social anxiety, and autistic-like behaviors.
• Physical characteristics: Some physical features associated with FXS include a long face, large ears, flat feet, and hyper-flexible joints.
• Learning difficulties: Language delays, difficulty with abstract concepts, and poor academic performance are often observed in individuals with FXS.

4. Diagnostic Approaches

Several diagnostic approaches can confirm the presence of Fragile X Syndrome:

• Molecular Testing: This involves analyzing the number of CGG repeats in the FMR1 gene using polymerase chain reaction (PCR) techniques. A result of over 200 CGG repeats confirms a full mutation.
• Family History: Evaluating the family history for individuals with FXS can provide valuable information, as the disorder is inherited.
• Clinical Evaluation: A comprehensive clinical evaluation is crucial for assessing the presence of characteristic physical features, developmental delays, and behavioral challenges associated with FXS.

Conclusion

FXS is a genetic disorder caused by an expansion of the CGG repeat within the FMR1 gene on the X chromosome. The disorder follows an X-linked dominant inheritance pattern and has a wide range of clinical presentations. Molecular testing, family history assessment, and clinical evaluation are essential for diagnosing Fragile X Syndrome.