Holoprosencephaly

Holoprosencephaly (HPE) can be inherited, but it is not always inherited.

Inherited causes of holoprosencephaly may include:^[1]

• certain types of chromosome abnormalities
• single gene mutations that cause syndromic disorders
• mutation(s) in a gene associated with isolated (nonsyndromic) HPE

The risk for family members to have HPE depends on the specific cause of HPE in the family, if known.^[1] For example, nonsyndromic HPE is usually inherited in an autosomal dominant manner.^[2] This means that having a variation (mutation) in only one copy of the responsible gene in each cell is enough to cause the condition. When a person with a mutation that causes an autosomal dominant condition has children, each child has a 50% (1 in 2) chance to inherit that mutation. However, not all people with a gene mutation that causes HPE will have HPE.^[2] This is called reduced penetrance.

For people with HPE without a known cause, recurrence risk for family members is likely to be low, but may be as high as 50%.^[1] 

People with personal questions about recurrence risks for themselves or family members are encouraged to speak with a genetic counselor or other genetics professional.

The genetic risk to siblings of a person with HPE depends on the genetic status of their parents.^[1]

Some people with autosomal dominant nonsyndromic HPE have an affected parent. If a parent is affected, or has a mutation that causes autosomal dominant HPE (even with no features), the risk for each sibling to inherit the mutation is 50% (1 in 2). If a person does not inherit a mutation from a parent with a mutation, that person cannot pass the mutation on to his/her children (i.e. the mutation has been eliminated from that lineage).

Others with HPE are affected due to having a new mutation in the responsible gene (not inherited from a parent). If the parents are unaffected and the family history is negative, the risk for siblings of an affected person to carry a mutation appears to be low.^[1]

It is possible for someone to have a mutation associated with HPE and be unaffected. Not everyone with a mutation that causes HPE will have HPE; this phenomenon is called reduced penetrance.^[2] Furthermore, the features of people with mutations in genes associated with nonsyndromic HPE can vary greatly, even within the same family. For example, a mutation may cause the severest form of HPE in one family member, while appearing not to cause any abnormalities in another.

A careful family history by a clinical geneticist familiar with HPE is important for affected families in order to establish who might be at risk to carry or inherit a mutation associated with HPE.

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.