Mosaicism and Fragile X Syndrome Overview

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Questions and Answers

Which of the following describes the inheritance pattern of Duchenne muscular dystrophy?

X-linked recessive inheritance pattern (correct)

Autosomal recessive inheritance pattern

Mitochondrial inheritance pattern

Autosomal dominant inheritance pattern

What characterizes a genetic disorder exhibiting anticipation?

Symptoms worsen and appear at an earlier age in successive generations (correct)

Symptoms remain constant across generations

Only males are affected by the disorder

Symptoms decrease in severity with each generation

In X-linked recessive disorders, which of the following is true?

Affected males can transmit the disorder to their sons

Carrier females will always express the disorder

Both males and females are affected equally

Daughters of affected males will be obligate carriers (correct)

Which condition is characterized by females with a partial or missing X chromosome?

Turner syndrome Signup and view all the answers

What does locus heterogeneity in genetic disorders refer to?

Several genes can cause the same phenotype Signup and view all the answers

What is the primary mechanism that leads to X-inactivation in females?

X-Inactive-Specific Transcript (XIST) Signup and view all the answers

Which of the following conditions is associated with Klinefelter syndrome?

47, XXY karyotype Signup and view all the answers

What is a common phenotypic feature of Turner syndrome?

Sexual immaturity Signup and view all the answers

Which of the following accurately describes the consequences of X-inactivation?

It causes functional hemizygosity in females. Signup and view all the answers

What is a significant feature of genetic testing in X-chromosome aneuploidies?

It detects both Klinefelter and Turner syndromes. Signup and view all the answers

What would indicate a skewed X-inactivation pattern in females?

Preferential inactivation of the father’s X chromosome. Signup and view all the answers

Which biochemical evidence supports X-inactivation?

Variation in G6PD allele migration. Signup and view all the answers

What reproductive challenge is typically faced by individuals with Klinefelter syndrome?

Infertility. Signup and view all the answers

What is the primary genetic cause of Fragile X syndrome?

Expansion of CGG repeats in the FMR1 gene Signup and view all the answers

Which condition is characterized by the presence of an abnormal number of sex chromosomes, specifically a karyotype of 45X/46XX?

Turner syndrome Signup and view all the answers

What is the Sherman Paradox in relation to Fragile X syndrome?

It explains how normal transmitting males can pass on expanded CGG repeats. Signup and view all the answers

What is the role of the Y chromosome in males concerning Turner syndrome?

It provides essential genes that prevent Turner syndrome. Signup and view all the answers

Which findings indicate the need for chromosome or chromosome microarray analysis?

Unexplained intellectual disability or autism Signup and view all the answers

How do CGG repeat expansions correlate to the risk of Fragile X syndrome across generations?

The risk increases due to repeat instability, particularly in female meiosis. Signup and view all the answers

In assessing family risk for Fragile X syndrome, which population is considered obligate heterozygotes?

Daughters of normal transmitting males Signup and view all the answers

Which of the following is NOT a typical indication for chromosome analysis?

Single congenital anomaly Signup and view all the answers

Study Notes

Mosaicism and Chromosomal Disorders

Mosaicism observed in cases like 45X/46XX, where mitotic nondisjunction (NDJ) occurs.
Presence of Y chromosome material in absence of cell line indicates risk for virilization and sex cord tumors.
Turner syndrome (45X) not seen in males due to requirement of X-linked genes for escape from inactivation, homologous Y chromosome, and essential genes to prevent the syndrome.

Fragile X Syndrome Pathogenesis

X-linked dominant disorder; monogenic disease affecting all body cells.
Caused by mutation at the fragile site FRAXA on Xq27.3, involves CGG repeat expansion in the 5' UTR of the FMR1 gene.
Methylation of the promoter leads to reduced protein production, causing RNA toxicity; males are always affected while about half of females may be cognitively impaired.
Repeats accumulate over generations (Sherman Paradox), with unstable CGG repeats expanding primarily during female meiosis.
Lower risk of expansion with shorter repeats and presence of AGG interruptions.
Daughters of normal transmitting males are obligate heterozygotes but typically do not show intellectual disabilities.

Indications for Chromosomal Analysis

Chromosome or chromosome microarray analysis indicated for known or suspected chromosomal abnormalities.
Recommended for cases of multiple congenital anomalies, growth retardation, or developmental delays.
Also indicated for unexplained intellectual disabilities and autism.

X-Chromosome Inactivation

Females are mosaic due to X chromosome inactivation, causing each cell to be functionally hemizygous.
Example: Tortoiseshell cats displaying different colored fur confirming variable gene expression due to X-inactivation.
X-inactivation is early, random, complete, and propagated clonally.
Evidence includes: genetic (tortoise shell coat color), cytologic (Barr bodies), and biochemical (G6PD) variations.

Major Phenotypic Features of X-Chromosome Aneuploidy

X-chromosome aneuploidy results in conditions such as Klinefelter syndrome (XXY) and Turner syndrome (45X).
Klinefelter syndrome characterized by male phenotype, small testes, infertility, social interaction challenges, and potential intellectual disabilities due to paternal or maternal NDJ.
Turner syndrome presents with amenorrhea, sexual immaturity, and gonadal dysgenesis; often results in abortive pregnancies.
Karyotype abnormalities include 45X (50%) and 46,X (15%), with patients often being mosaic for different repeat expansion lengths.

Inheritance Patterns

Autosomal Recessive: Horizontal inheritance; common chance occurrences; can be compounded by consanguinity, locus heterogeneity, and pseudodominance. Example: congenital hearing impairment.
X-Linked Recessive: Primarily affects males with carrier females; no male-male transmission. Example: Duchenne muscular dystrophy.
X-Linked Dominant: More females affected, males severely impacted; no male-male transmission.
Mitochondrial Inheritance: Maternal transmission; involves 37 genes with a higher mutation rate than nuclear DNA.

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Description

Explore the complexities of mosaicism and chromosomal disorders like Turner syndrome and Fragile X syndrome. This quiz covers the genetic mechanisms behind these conditions, including the impact of CGG repeat expansions and the implications for individuals affected by these disorders. Test your understanding of these important topics in genetics and their clinical significance.