In our last post, we looked at what genes are and how changes in them can lead to Primary Immunodeficiency (PI). But how do doctors find these changes? Genetic sequencing is one of the tools doctors use to identify genetic variants and diagnose Primary Immunodeficiency. In this post, we will explore how genetic sequencing works and why it matters for people with Primary Immunodeficiency. 

Want to learn more about genetics? Read our What is a Gene? blog post here.

DNA is your body’s instruction manual. This manual is written with chemical building blocks called bases, each represented by a letter: A, C, G, and T. Genetic sequencing means reading the order of these bases in a person’s individual DNA. You can think of it as reading the spelling of DNA, letter by letter, to see whether anything is out of place.

Genetic sequencing reads a person’s unique DNA spelling, or sequence, and compares it to a standard reference sequence to find any differences between the two. These differences are called variants. Some variants have no impact on a person, while others can change how a gene works.

How Does Genetic Sequencing Work?

Sequencing often starts with a blood or saliva sample. The lab extracts DNA from the sample, and a sequencing machine reads it in many small pieces. Next-generation sequencing reads millions of small fragments at once, allowing much more DNA to be analyzed in less time than traditional sequencing methods.

A computer then lines up the pieces, compares them to the reference, and flags the variants. Specialists review those variants alongside the patient’s symptoms and medical history to decide which ones, if any, could explain a patient's condition. 

What Types of Genetic Sequencing Are Used for Primary Immunodeficiency?

Doctors can choose from several approaches, depending on the patient and what they are looking for:

  • Single-gene testing examines one gene and is used when a doctor suspects a specific condition.
  • Gene panels examine a selected group of genes known to be linked to Primary Immunodeficiency.
  • Exome sequencing examines the parts of genes that carry instructions for building proteins.
  • Genome sequencing examines a person’s entire DNA.

These sequencing methods can also be done as family testing, where a patient and their parents are sequenced together, which can improve the chances of finding an answer.

How Does Genetic Sequencing Help Diagnose Primary Immunodeficiency?

There are over 550 identified genetic variants that cause Primary Immunodeficiency. Sequencing can lead to a genetic diagnosis, which can confirm the condition a person has, guide treatment decisions, support genetic counseling, and allow at-risk relatives to be tested. 

Can Genetic Sequencing Find an Answer for Everyone?

Not always. Across studies of people with Primary Immunodeficiency, genetic testing finds a cause in about 29% of patients on average, with results ranging from 10% to 70% depending on the group tested and the method used.

Sometimes a test finds a variant whose effect is unclear, and new genes linked to Primary Immunodeficiency are still being discovered. For that reason, results can be reviewed again as the science advances. A test that does not find a cause does not rule out Primary Immunodeficiency, and doctors combine genetic results with a patient's medical history and other immune tests to form a diagnosis.

How Does the Jeffrey Modell Foundation Help Make Genetic Sequencing Possible?

Jeffrey's Insights is a no-cost genetic sequencing program for physicians in the Jeffrey Modell Centers Network who are caring for patients with suspected Primary Immunodeficiency but no genetic diagnosis. Since the program launched in 2019, it has sequenced more than 7,000 patients and identified more than 58,000 genetic variants. After sequencing, 33% of patients have had a change in treatment and 31% have had a change in outcome. You can learn more about Jeffrey’s Insights in our latest publication in the Journal of Human Immunity.

Patients can ask their immunologist whether genetic sequencing is right for them. You can find an immunologist near you with our Find an Expert tool.

Want to Learn More?

Learn more about genetic sequencing here:

DNA Sequencing Fact Sheet (NIH)

What is Genomic Sequencing? (CDC)

If you missed the first post in our genetic sequencing series, read What Is a Gene? 

If you think you or your child may have Primary Immunodeficiency, the best next step is to talk with a doctor.