What Is the Recurrence Risk for Holoprosencephaly?

If you are planning to have another baby after having a child with holoprosencephaly (HPE), it is entirely natural to wonder if it will happen again, and what you can do to prevent it. The chances of having another child with HPE depend on the underlying cause, which can be genetic or environmental.

The recurrence risk for future pregnancies ranges from less than 1% to as high as 50% ^[1]. It is incredibly important to remember that random genetic errors or chromosomal changes are not caused by anything you did or didn’t do during your pregnancy.

To understand your specific recurrence risk and your family planning options, it is helpful to know which of the following scenarios applies to your family:

Chromosomal Causes: Generally a Low Risk

In many cases, HPE is caused by a chromosomal abnormality, such as Trisomy 13 (having three copies of chromosome 13 instead of two). These types of numerical chromosomal errors are random, one-time events that happen during the formation of an egg or sperm ^[1].

If your child’s HPE was caused by a random chromosomal abnormality like Trisomy 13, and both parents have normal chromosomes, the recurrence risk for future pregnancies is low—around 1% ^[2]. This risk is only slightly higher than the general population.

Gene Mutations: Up to a 50% Risk

Sometimes, HPE is caused by a spelling mistake in a single gene that provides instructions for early brain development. Common genes linked to HPE include SHH, ZIC2, and SIX3.

If one parent carries a mutation in one of these HPE-associated genes, there is up to a 50% chance in each pregnancy of passing that mutation on to the baby ^[1][3].

However, genetic inheritance with HPE can be highly unpredictable due to two important concepts ^[4]:

• Variable expressivity: People with the exact same gene mutation can have very different symptoms. A parent carrying an HPE mutation might only have minor physical signs (called microforms), such as a single central front tooth, closely set eyes, or a poor sense of smell ^[5]. Their child, however, might inherit the same mutation and have severe HPE.
• Incomplete penetrance: Sometimes, a person can inherit the gene mutation but show absolutely no signs or symptoms of the condition at all ^[4].

Because of these factors, a parent might be a “silent” carrier of an HPE gene mutation without ever realizing it.

Environmental Causes: Maternal Diabetes

While many causes of HPE are genetic, the environment in the womb during the very first weeks of pregnancy also plays a significant role. Maternal pregestational diabetes (diabetes that exists before pregnancy) is a major risk factor, increasing the chance of HPE up to 200 times compared to the general population ^[6][7].

If your previous child’s HPE was linked to pregestational diabetes, the recurrence risk in a future pregnancy is strongly tied to your glycemic (blood sugar) control ^[7]. Working with your medical team to tightly control your blood sugar before conception and during the first trimester can significantly lower the risk of HPE happening again ^[8].

“New” (De Novo) Mutations

If genetic testing shows that your child has a gene mutation, but high-sensitivity testing of both parents shows that neither parent carries the mutation in their blood, it is called a de novo (new) mutation ^[9].

In these cases, the mutation happened for the first time in the child. The recurrence risk drops significantly and is very low. However, it is not exactly zero. There is a rare phenomenon called germline mosaicism, where the mutation exists only in a parent’s reproductive cells (eggs or sperm) but not in their blood ^[10][9]. Because of this small possibility, specialists still offer prenatal screening in future pregnancies.

Unexplained (Idiopathic) Cases

Sometimes, even after exhaustive genetic testing, doctors cannot find the exact cause of a child’s HPE. In these idiopathic cases, where both chromosomal and single-gene testing come back normal, the empirical recurrence risk for future pregnancies is generally estimated at approximately 2% to 5% ^[3][9]. This accounts for the possibility of undetected low-level mosaicism or complex interactions between multiple minor genetic and environmental factors ^[11][12].

Why Counseling and Testing Are Critical

Because the recurrence risk can be as low as 1% or as high as 50%, working with a genetic counselor or medical geneticist is absolutely essential for family planning ^[1]. This testing process typically takes a few weeks to several months and involves:

1. Testing the affected child first to identify the specific genetic or chromosomal cause.
2. Testing both parents (via blood or saliva) to see if either carries the genetic change.
3. A thorough physical exam of the parents to look for mild signs (microforms) of HPE ^[13].

Proactive Options for Future Pregnancies

If a specific genetic mutation is identified in your family, you may have proactive reproductive options to prevent passing the condition on. In Vitro Fertilization (IVF) with Preimplantation Genetic Testing (PGT-M) allows doctors to test embryos for the specific familial mutation before they are transferred to the uterus ^[9][14]. This can reduce the risk of having another affected pregnancy to near zero.