X-Linked Inheritance ✅ Flashcards
What causes X-linked recessive disorders?
Mutations in genes on the X chromosome
What is the result of the mutation being on the X-chromosome in X-linked recessive disorders?
It causes disease in males and leaves females unaffected or only mildly affected
Where does the mutation come from in a boy affected by an X-linked recessive disorder?
Either inherited from mother or can occur de novo
What is the % chance of a mother who is a carrier of an X-linked recessive disorder having an affected child?
25%
Why is there a 25% chance of a mother who is a carrier of an X-linked recessive disorder having an affected child?
50% chance that she will pass on the affected chromosome, and 50% chance the offspring will be male
What is the % chance a mother who is a carrier of an X-linked recessive disorder will have a carrier daughter?
25%
What is the implication of having a de novo mutation causing an X-linked recessive disorder compared to inheriting the mutation from a carrier mother?
The risk of a further affected child is lower
What is the usual risk of recurrence of a de novo mutation in a future child?
1%
Why is the recurrence risk of de novo mutations in a future child higher than 1% for some X-linked recessive disorders?
Due to gonadal mosaicism
Give an example of an X-linked recessive disorder where the recurrence risk of a de novo mutation in a future child is higher than 1%
Duchenne muscular dystrophy
Can a man with a X-linked recessive disorder pass the condition on to his sons?
No
Why can a man with an X-linked recessive disorder not pass the condition on to his son?
Because the man only passes on his Y chromosome
What is the inheritance of Fragile X syndrome?
X-linked recessive
What is the frequency of fragile X syndrome?
1 in 2000
What causes Fragile X syndrome?
A triplet repeat expansion in the FMR1 gene
Does fragile X syndrome show anticipation?
Yes
What repeat length is ‘full mutation’ and causes disease in fragile X syndrome?
> 200
What are repeat lengths of 55-200 known as in Fragile X syndrome?
‘Premutations’
What is the clinical relevance of premutations in Fragile X syndrome?
Repeats can expand when transmitted to a child to become a full mutation
What are the features of Fragile X syndrome?
- Moderate learning difficulties
- Relative macrocephaly
- Mitral valve prolapse
Can females have Fragile X syndrome?
They can show features of the condition, but they are milder than males
How is a diagnosis of Fragile X syndrome made?
Targeted genetic testing for expansion of the FMR1 gene
What are X-linked dominant disorders caused by?
Mutations in genes on the X chromosome
Are X-linked dominant disorders more common in females or males?
Females
Why are X-linked dominant disorders more common in females?
Because the mutation is frequently lethal in males, often soon after conception
How can X-linked dominant mutations be obtained?
- Inherited from affected mother
- De novo mutation
What is the % chance of a woman with an X-linked dominant disorder passing it on to their daughter?
50%
What is the risk that a surviving male is affected by an X-linked dominant disorder?
Very low (for most X-linked dominant disorders)
What is the risk of recurrence in a future child of de novo mutations causing X-linked dominant disorders?
1%
What does the 1% risk of recurrence in a future child of a de novo mutation causing an X-linked dominant disorder?
The small risk of gonadal moasacism
What is the inheritance pattern of Rett syndrome?
X-linked dominant
What is the incidence of Rett syndrome?
1 in 10,000-20,000 females
What is Rett syndrome caused by?
A heterozygous loss-of-function mutation in the MECP2 gene
Is the mutation in Rett syndrome inherited or de novo?
De novo
What is the risk of recurrence of Rett syndrome in a future child?
1%
What are the features of Rett syndrome?
Apparent normal early development followed by a period of regression and loss of language and motor skills, accompanied by deceleration of head growth at 6-18 months
What stereotypical movements are seen in Rett syndrome?
Midline hand movements
Are seizures common in Rett syndrome?
Yes
How is Rett syndrome diagnosed?
Molecular genetic testing with sequencing and copy number analysis of the MECP2 gene
