Clinical Immunology · Agammaglobulinemia, early-onset, with hypertrophic cardiomyopathy and neutropenia

Diagnostic Tests and Genetics

At a Glance

FNIP1 deficiency is diagnosed using immune blood tests, repeated CBCs for low neutrophils, heart imaging and electrical testing, and genetic testing that can detect both small changes and larger missing or duplicated gene sections.

Diagnosing FNIP1 deficiency requires a detailed investigation into how your child’s immune system and heart are functioning. Because this condition involves two very different systems in the body, your medical team will use a combination of blood work, advanced imaging, and specialized genetic testing to confirm the diagnosis ^[1]^[2].

Immunological and Blood Testing

The first step in diagnosing this condition usually involves checking the “army” of white blood cells and antibodies that protect your child from infection.

Quantitative Immunoglobulins: This blood test measures the levels of antibodies (IgG, IgA, and IgM). In children with FNIP1 deficiency, these levels are typically extremely low or absent, a condition known as agammaglobulinemia. Your doctor will interpret these tests based on your child’s age, maternal antibodies (in infants), and whether IVIg has been given ^[1]^[3].
B-Cell Flow Cytometry: This is a specialized test that counts specific types of white blood cells. Doctors look for CD19+ and CD20+ B cells. In this condition, these cells are often severely reduced or completely missing ^[1]^[2].
Serial CBCs: A Complete Blood Count (CBC) with a differential measures neutrophils, another type of infection-fighting cell. Because neutropenia (low neutrophils) in this condition can be intermittent—meaning it comes and goes—doctors often need to perform “serial” (repeated) tests over several weeks to catch it ^[1]^[3].

Cardiac Imaging and Monitoring

Because FNIP1 deficiency can cause the heart muscle to thicken, several tests are used to monitor the heart’s structure and electrical activity.

Echocardiogram: This is an ultrasound of the heart and is the primary tool used to identify hypertrophic cardiomyopathy (HCM). It allows doctors to measure the thickness of the heart walls and see how well the heart is pumping blood ^[2]^[4].
Electrocardiogram (ECG): This test records the electrical signals in the heart. Doctors look for a Wolff-Parkinson-White (WPW) pattern, which indicates an extra electrical pathway that can increase the risk of a dangerously fast heart rate, though it does not mean the child is currently having a dangerous event ^[4]^[3].
Cardiac MRI: If the echocardiogram shows thickening, a Cardiac MRI may be performed to get a more detailed look at the heart muscle and check for fibrosis (scarring), which can affect the heart’s long-term health ^[4].

The Role of Genetics

The most definitive way to diagnose this condition is through genetic testing to find mutations in the FNIP1 gene. However, a simple sequencing test might miss the cause.

Exome or Genome Sequencing: These tests (WES or WGS) read the genetic “code” to look for small errors or “typos” in the FNIP1 gene ^[2].
Copy Number Variant (CNV) Analysis: In some children, a whole section of the gene is missing (deletion) or doubled (duplication) rather than just misspelled ^[1]. A standard sequence test can sometimes overlook these large changes, so you should discuss with your geneticist whether CNV analysis is needed, although some advanced exome pipelines may already include it ^[1].
Parental Testing and Genetic Counseling: Doctors often test both parents to confirm that the child inherited one non-working copy of the gene from each, which is the hallmark of this autosomal recessive condition. A genetic counselor can also discuss carrier testing for relatives and recurrence risk ^[1].

Diagnostic Completeness Checklist

You can use this checklist to track the tests your child has completed. Having these results organized will help you when meeting with different specialists.

Test Category	Specific Test	What it Confirms	Status
Immune	Flow Cytometry	Assessment of CD19+/CD20+ B cells ^[1]	[ ]
Immune	IgG, IgA, IgM	Agammaglobulinemia (low antibodies) ^[3]	[ ]
Blood	Serial CBCs	Intermittent or chronic neutropenia ^[1]	[ ]
Heart	Echocardiogram	Hypertrophic cardiomyopathy (thickening) ^[4]	[ ]
Heart	ECG	Pre-excitation or WPW pattern ^[3]	[ ]
Genetics	WES/WGS + CNV	Biallelic FNIP1 mutations/deletions ^[1]	[ ]

Common questions in this guide

What tests are used to diagnose FNIP1 deficiency?

Doctors usually combine quantitative IgG, IgA, and IgM testing with B-cell flow cytometry for CD19+ and CD20+ cells. Serial complete blood counts can look for intermittent neutropenia, while echocardiograms and ECGs assess heart involvement. Genetic testing of FNIP1 helps confirm the diagnosis.

Why might my child need CNV analysis as well as FNIP1 sequencing?

Sequencing looks for small changes in the FNIP1 genetic code, but it may miss a larger section that is deleted or duplicated. CNV analysis is designed to detect these larger changes. Some exome testing systems already include CNV analysis, so ask whether it was part of the test.

How are heart problems checked in FNIP1 deficiency?

An echocardiogram uses ultrasound to measure heart-wall thickness and how well the heart pumps. An ECG checks for a Wolff-Parkinson-White pattern or other electrical findings. If the heart muscle is thickened, cardiac MRI may provide more detail and look for scarring.

Can one normal CBC rule out neutropenia?

No. Neutropenia in FNIP1 deficiency can come and go, so doctors may repeat a complete blood count with a differential over several weeks. Repeated results help show whether low neutrophils are intermittent or persistent.

What genetic result supports a diagnosis of FNIP1 deficiency?

The diagnosis is supported when testing finds disease-causing changes affecting both copies of the FNIP1 gene. Testing both parents can show whether the child inherited one non-working copy from each parent, which is the expected autosomal recessive pattern. A genetic counselor can explain what the specific result means.

Could IVIg or maternal antibodies affect antibody test results?

Yes. Doctors interpret immunoglobulin results based on the child’s age, maternal antibodies in infants, and whether intravenous immunoglobulin (IVIg) or other replacement therapy was given. Tell the care team when treatment was given so the results are interpreted in context.

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References (4)

1
Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency.
Saettini F, Poli C, Vengoechea J, et al.
Blood 2021; (137(4)):493-499 doi:10.1182/blood.2020006441.
PMID: 32905580
2
A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy.
Spivak I, Lev A, Simon AJ, et al.
Immunogenetics 2024; (77(1)):2 doi:10.1007/s00251-024-01359-3.
PMID: 39537849
3
Clinical and Immunologic Features of a Patient With Homozygous FNIP1 Variant.
Ulaş S, Naiboğlu S, Özyilmaz İ, et al.
Journal of pediatric hematology/oncology 2024; (46(6)):e472-e475 doi:10.1097/MPH.0000000000002862.
PMID: 38748614
4
Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome.
Niehues T, Özgür TT, Bickes M, et al.
European journal of immunology 2020; (50(7)):1078-1080 doi:10.1002/eji.201948504.
PMID: 32181500

This page is for informational purposes only and does not constitute medical advice. It explains diagnostic testing for a child with possible FNIP1 deficiency; your child’s immunology, cardiology, and genetics teams should interpret results and recommend next steps.