Is Alagille syndrome inherited, what is the risk of recurrence?

[Anonymous]

Is Alagille syndrome inherited, and what is the chance my other children or future children will be affected?

[Genetic Counselor]

Alagille syndrome follows an autosomal dominant pattern of inheritance, meaning that a change in just one of the two copies of either JAG1 or NOTCH2 that a person carries are enough to cause the condition; it does not require changes on both copies.

• In roughly sixty percent of individuals, the causative genetic change arose new in that person and was not inherited from either parent, a situation described as a de novo change.
• In the remaining approximately forty percent, the change was inherited from a parent who also carries it.
• Around ninety-six percent of people with a JAG1 change show at least some recognizable feature of Alagille syndrome, a measure called penetrance, though the feature may be as subtle as a heart murmur or a particular eye finding. Because of this, both parents of a newly diagnosed child should be carefully examined by a specialist, and ideally undergo genetic testing themselves, before either is told they do not carry the change.
• For an individual who has Alagille syndrome from any cause, each of their future children has a fifty percent chance of inheriting the same genetic change, although the severity in that child cannot be predicted in advance, even within the same family.
• In about eight percent of families, a parent who appears unaffected and tests negative on a blood sample may still carry the genetic change in only a portion of their reproductive cells, a situation called germline mosaicism. This means the chance of the condition recurring in future children is not zero even when parental testing looks reassuring.

Referral for genetic counseling is recommended so that risk can be assessed accurately for each specific family.

[Author]

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