Genetics and Interpreting the Lab Report

For many years, the cause of Aagenaes syndrome was a mystery. Today, advancements in genetic testing have provided a clear answer: a change in the UNC45A gene supports the diagnosis ^[1]. This discovery has transformed how we approach the condition, allowing families to get answers much earlier—often while their child is still an infant ^[1][2].

The Diagnosis: UNC45A

Aagenaes syndrome is an autosomal recessive disorder, meaning a child must inherit two altered copies of the UNC45A gene (one from each parent) to have the condition ^[1]. Diagnosis should be framed as a compatible clinical phenotype plus biallelic pathogenic or likely pathogenic UNC45A variants, with interpretation by a genetics professional.

While most standard genetic tests look at the “coding” parts of a gene—the parts that provide direct instructions for proteins—the primary cause of Aagenaes syndrome is often found in the 5’-UTR (5’-untranslated region) ^[1]. This is a “control region” of the gene that regulates how much protein is made. Make sure your doctor knows a standard coding-only panel may miss this common 5’-UTR variant.

• The c.-98G>T or c.-88G>A Variants: These indicate the exact “address” of the genetic change. They act like a “dimmer switch,” significantly lowering the amount of UNC45A protein in the liver and lymphatic cells ^[1].
• Homozygous vs. Compound Heterozygous: Your child’s report will likely use one of these two terms. Homozygous means they have the same variant (like c.-98G>T) on both copies of the gene. Compound heterozygous means they have two different variants—for example, the c.-98G>T variant on one copy and a different “loss-of-function” variant on the other ^[1][2].

Why Early Testing Matters

One of the most valuable roles of genetic testing is its ability to help establish a diagnosis of Aagenaes syndrome before lymphedema (leg swelling) even begins ^[1].

Because the liver symptoms usually appear first, doctors may order a neonatal cholestasis gene panel ^[3]. This is a single test that checks dozens of different genes known to cause liver issues in babies. If the test identifies the UNC45A variants alongside compatible symptoms, it supports that the baby has Aagenaes syndrome. This allows parents and doctors to know that leg swelling may develop later in childhood, rather than being surprised by it years down the road ^[1].

However, a biallelic UNC45A result does not replace urgent assessment for biliary atresia or other treatable causes of infant liver issues, which require rapid clinical, laboratory, and imaging work-up.

Distinguishing Aagenaes from “Look-Alikes”

There are other rare conditions that involve both liver issues and lymphedema, and genetic testing helps tell them apart.

The most common “look-alike” is Hennekam syndrome (also known as LCS2). While the symptoms may look similar, Hennekam syndrome is caused by mutations in the CCBE1 gene (or sometimes FAT4 or ADAMTS3) ^[4]. It often involves additional symptoms, such as unique facial features or intellectual disability, which are not typically part of Aagenaes syndrome ^[4]. Identifying the UNC45A variant helps confirm it is Aagenaes (LCS1) and not one of these other conditions.

Navigating the Lab Report

When you look at your child’s genetic report, it can be helpful to focus on these key areas:

1. Gene Name: Look for UNC45A.
2. Variant Description: You may see codes like c.-98G>T or c.-88G>A, which should be reported with the transcript and evidence for pathogenicity ^[1][2].
3. Classification: Variants are usually labeled as Pathogenic (disease-causing) or Likely Pathogenic. If a variant is labeled as a Variant of Uncertain Significance (VUS), a single variant, or a negative test, it does not confirm the condition, and you should discuss this carefully with a genetic counselor ^[2].
4. Testing the Parents: Doctors often recommend testing both parents (called “segregation testing”). This confirms that the child inherited one variant from each parent, which is the hallmark of an autosomal recessive diagnosis ^[1]. Genetic testing should be ordered or interpreted with a genetic counselor.