Medical Genetics · Branchio-Oto-Renal Syndrome

The Genetics of BOR Syndrome: How It Happens

At a Glance

BOR syndrome is a genetic condition primarily caused by mutations in the EYA1, SIX1, or SIX5 genes, which affect how the ears, neck, and kidneys develop. It is inherited in an autosomal dominant pattern, meaning a parent with the gene has a 50% chance of passing it to their child.

The physical features of Branchio-Oto-Renal (BOR) syndrome are caused by specific “instructional errors” in a child’s DNA. To help your child develop in the womb, genes must work together like a construction crew. In BOR, a few key “workers” have the wrong instructions, which changes how the ears, neck, and kidneys are built ^[1]^[2].

The Genetic Construction Crew: EYA1, SIX1, and SIX5

Three main genes are currently known to be responsible for the BOR spectrum. These genes provide instructions for proteins that act as transcription factors—essentially “master switches” that turn other genes on or off at the right time during development ^[1]^[3].

EYA1: This is the most common gene involved, found in about 40% of cases ^[1]. EYA1 works closely with the SIX1 gene to build the inner ear and kidneys ^[1]^[4]. When EYA1 has a mutation, it often leads to a specific inner ear shape known as an unwound or offset cochlea (the hearing organ is slightly rotated or “loosened” in shape) ^[5]^[6].
SIX1: This gene is the primary partner for EYA1. Mutations here are less common and often result in a slightly different pattern: children with SIX1 mutations tend to have fewer kidney problems and fewer middle ear issues compared to those with EYA1 mutations ^[7]^[2].
SIX5: This is a rarer cause of BOR, and researchers are still learning exactly how it contributes to the syndrome ^[1]^[8].

How BOR is Inherited

BOR syndrome follows an autosomal dominant inheritance pattern. This sounds complicated, but it can be broken down into a few simple facts:

Only one copy is needed: We have two copies of most genes (one from each parent). “Dominant” means that only one copy of the gene needs to have a mutation to cause the syndrome ^[9]^[10].
The 50/50 Rule: If blood tests confirm that a parent carries the mutation, there is a 50% chance with each pregnancy that the child will inherit it ^[9]^[11].
Variable Expressivity: This is a vital concept for families. It means that the same gene mutation can look very different in different people ^[12]. A parent might only have a tiny pit in front of their ear, while their child might have significant hearing loss and kidney issues ^[9]^[13].
De Novo Mutations: In some cases, the mutation is “de novo,” meaning it is brand new in the child ^[14]^[15]. Neither parent has the gene, and the risk to future children from those parents is extremely low.

Because of this inheritance pattern, it is highly recommended that both parents undergo genetic testing or at least a baseline kidney ultrasound and audiology exam. This helps determine if either parent has a mild, previously undiagnosed form of the syndrome ^[16].

The Role of Genetic Testing

Genetic testing can confirm a diagnosis, but it doesn’t always provide an answer immediately.

Standard Sequencing: This looks for small “typos” in the genes. It finds a mutation in about 50% of patients ^[16]^[8].
Copy Number Variants (CNVs): Sometimes, a whole chunk of a gene is missing rather than just having a small typo. About 20% of BOR patients have these larger “missing pieces” (deletions), which require a special test called MLPA to find ^[16].
What if testing is negative? If standard tests find nothing, it does not mean your child doesn’t have BOR. It simply means our current technology hasn’t found the specific “typo” yet. In these cases, doctors may recommend whole-exome sequencing or whole-genome sequencing to look at every gene in the body ^[17]^[16].

Why the Specific Gene Matters

Knowing which gene is involved can help your medical team tailor your child’s care. For example, because EYA1 mutations are more strongly linked to kidney issues, a child with that mutation may need more frequent kidney monitoring than a child with a SIX1 mutation ^[7]^[13]. Additionally, the offset cochlea seen in EYA1 cases can help surgeons plan more effectively if a cochlear implant is ever needed ^[6]^[18].

Common questions in this guide

What genes cause BOR syndrome?

BOR syndrome is primarily caused by mutations in the EYA1, SIX1, and SIX5 genes. These genes act as master switches during fetal development, providing the necessary instructions for building the ears, neck, and kidneys.

How is BOR syndrome inherited?

It follows an autosomal dominant inheritance pattern. This means only one copy of a mutated gene is needed to cause the syndrome. If a parent carries the mutation, there is a 50% chance with each pregnancy that their child will inherit it.

Can a child have BOR syndrome if neither parent has it?

Yes. In some cases, the condition is caused by a de novo mutation, which is a brand-new genetic change in the child. In these instances, neither parent carries the gene, and the risk to their future children is very low.

What does it mean if my child's genetic testing for BOR syndrome is negative?

A negative result on standard genetic testing does not rule out BOR syndrome. It simply means the specific genetic change has not been found with standard technology. Your doctor may recommend more comprehensive tests, like whole-exome sequencing, to find the exact mutation.

What does variable expressivity mean in BOR syndrome?

Variable expressivity means that the exact same gene mutation can cause very different physical features in different people. For example, a parent might only have a tiny ear pit, while their child could have significant hearing loss and kidney issues.

Curated prompts to bring to your next appointment.

1.Which specific gene mutation was identified in my child (EYA1, SIX1, or SIX5)?
2.Did the genetic testing include a search for Copy Number Variants (CNVs) or MLPA, or was it just standard sequencing?
3.If our initial genetic testing was negative, what is the next step — whole-exome sequencing or a larger gene panel?
4.Based on the gene identified, are there specific risks for kidney issues or particular types of hearing loss we should be more vigilant about?

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

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This page explains the genetics of BOR syndrome for educational purposes only. Always consult a genetic counselor or medical geneticist to interpret specific genetic test results or discuss inheritance risks for your family.

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