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PubMed This is a summary of 6 peer-reviewed journal articles Updated
Medical Genetics

Genetics & Biology: The PIGN Gene & Inheritance

At a Glance

Fryns syndrome is an autosomal recessive genetic condition caused by variants in the PIGN gene, which disrupts the development of vital organs like the diaphragm and lungs. Because both parents must be carriers, there is a 25% chance of the condition occurring in each pregnancy.

Understanding the biology behind Fryns syndrome can be a helpful way to process the diagnosis. It is important to remember from the start: nothing you did or did not do caused this. Genetic conditions like Fryns syndrome are the result of basic biological instructions that happen long before a child is born.

The PIGN Gene and its “Assembly Line”

The PIGN gene provides instructions for making a protein that plays a vital role in how cells develop. Think of this process like an assembly line in a factory.

The factory’s job is to build GPI anchors (glycosylphosphatidylinositol anchors). These anchors act like specialized “tethers” or “hooks” that hold other important proteins onto the surface of a cell [1][2]. Once these proteins are hooked to the cell surface, they help the body’s organs and systems develop correctly [3].

In Fryns syndrome, the PIGN gene is changed in a way that breaks this assembly line. Without these anchors, the body cannot correctly place the proteins it needs to build vital structures, such as the diaphragm or the lungs [2][4].

Severe vs. Milder Variants

Not every change to the PIGN gene is the same. Doctors look at the specific type of “mistake” in the gene code to understand the severity:

  • Biallelic-truncating variants: These are “stop” signs in the gene code that tell the cell to stop building the PIGN protein too early [4]. This usually results in a complete loss of the protein, leading to the most severe form of the condition, which is typical Fryns syndrome [2][4].
  • Missense variants: These are like “typos” where one letter of the code is replaced by another. The cell still builds the protein, but it may not work perfectly [4]. These variants often leave some residual (leftover) function, which can lead to a milder condition called MCAHS1 (Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 1) [2][5]. While children with MCAHS1 still face serious challenges like developmental delays and seizures, they are more likely to survive the newborn period [4].

How It Is Inherited

Fryns syndrome is an autosomal recessive condition. This means that for a child to be affected, they must inherit two changed copies of the PIGN gene—one from each parent [2][4].

In this scenario:

  • Both parents are carriers: You each have one working copy of the gene and one changed copy. Carriers typically have no health problems related to the condition and usually do not know they are carriers until they have an affected child.
  • The 25% Rule: For every pregnancy between two carriers, there is a:
    • 25% chance (1 in 4) the child will inherit two changed genes and have Fryns syndrome.
    • 50% chance (2 in 4) the child will be a carrier like the parents.
    • 25% chance (1 in 4) the child will inherit two working genes and not be a carrier or have the syndrome.

This recurrence risk remains the same for every pregnancy, regardless of the outcome of previous pregnancies. Knowing this allows you to discuss family planning options, such as specialized testing, with a genetic counselor [6].

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Common questions in this guide

What is the role of the PIGN gene in Fryns syndrome?
The PIGN gene provides instructions for making proteins that help organs develop properly. In Fryns syndrome, changes in this gene disrupt the cellular assembly line, preventing structures like the diaphragm and lungs from forming correctly.
How is Fryns syndrome inherited?
Fryns syndrome is an autosomal recessive condition. This means both parents must be carriers of a changed PIGN gene, and there is a 25 percent chance in each pregnancy for the child to inherit two changed genes and have the condition.
What is the difference between severe and mild PIGN gene variants?
Severe variants completely stop the PIGN protein from working and cause typical Fryns syndrome. Milder variants allow some protein function and can lead to a condition called MCAHS1, where children are more likely to survive the newborn period.
Will being a carrier of Fryns syndrome affect my own health?
No, carriers of the PIGN gene mutation typically do not have any health problems related to the condition. Most people do not know they are carriers until they have a child diagnosed with Fryns syndrome.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.What were the specific types of PIGN gene changes (variants) found in our child?
  2. 2.Are the variants biallelic-truncating or missense, and what does that mean for the severity?
  3. 3.Can you confirm that we are both carriers of these specific gene changes?
  4. 4.What are our options for genetic testing in a future pregnancy?

Questions For You

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References

References (6)
  1. 1

    PIGN prevents protein aggregation in the endoplasmic reticulum independently of its function in the GPI synthesis.

    Ihara S, Nakayama S, Murakami Y, et al.

    Journal of cell science 2017; (130(3)):602-613 doi:10.1242/jcs.196717.

    PMID: 27980068
  2. 2

    Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome.

    Alessandri JL, Gordon CT, Jacquemont ML, et al.

    European journal of human genetics : EJHG 2018; (26(3)):340-349 doi:10.1038/s41431-017-0087-x.

    PMID: 29330547
  3. 3

    Systems genetics reveals the influence of expression QTLs in mouse embryonic stem cells on transcriptional variation later in differentiated neural progenitor cells.

    Aydin S, Skelly DA, Dewey HB, et al.

    G3 (Bethesda, Md.) 2025; (15(7)) doi:10.1093/g3journal/jkaf099.

    PMID: 40327589
  4. 4

    Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.

    Loong L, Tardivo A, Knaus A, et al.

    Genetics in medicine : official journal of the American College of Medical Genetics 2023; (25(1)):37-48 doi:10.1016/j.gim.2022.09.007.

    PMID: 36322149
  5. 5

    A PIGN mutation responsible for multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) in an Israeli-Arab family.

    Khayat M, Tilghman JM, Chervinsky I, et al.

    American journal of medical genetics. Part A 2016; (170A(1)):176-82 doi:10.1002/ajmg.a.37375.

    PMID: 26364997
  6. 6

    Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH.

    Scott TM, Campbell IM, Hernandez-Garcia A, et al.

    Journal of medical genetics 2022; (59(3)):270-278 doi:10.1136/jmedgenet-2020-107317.

    PMID: 33461977

This page explains the genetics of Fryns syndrome for educational purposes. Always consult a genetic counselor or your medical team to interpret specific PIGN gene variants and understand your family planning options.

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