Genetics with Background


Chromosomes are large molecules that mainly consist of DNA. Genes are short parts of a chromosome that contain the genetic code for heritable characteristics. Some characteristics such as heightare influenced by many genes, and some just by one single gene. Two copies exist for most genes including those associated with PFIC.


A change in the genetic code is called a mutation. Mutations happen frequently. Some mutations are harmless, but some mutations can cause disease. The different subtypes of PFIC are due to mutations of a variety of specific single genes

Recessive & Dominant Genes:

Some genetic diseases are due to mutations in a single gene. A person can have harmful mutations in one copy or both copies of the gene. Diseases that require two defective copies of a gene are referred to as recessive diseases. Individuals with a single affected recessive gene are “carriers” of the disease – as their offspring are at risk of having the disease even though the parents do not have the disease (see diagram).

This is in contrast to dominant disorders. In these disorders a single defective copy of the gene can lead to disease. The impact of that defective copy is dominant over the other copy which is normal.

PFIC in general is a recessive disease and a person is only affected if she/he carries two mutated versions of the gene. PFIC3 (MDR3) disease in contrast can have features of either a recessive or a dominant disease and as such clinical features of the disease may exist in individuals with only one defective copy of the gene. In certain circumstances of biological stress (e.g.pregnancy, infection, response to certain medications) individuals with only one affected copy of a recessive gene may develop symptoms of that defect.

Inheritance of PFIC

The male sperm cell and the female egg cell only have one copy of each gene, therefore each offspring inherits only one copy of the father’s gene and one copy of the mother’s gene. The chance of inheriting one of the copies of the mother’s and father’s two copies of the gene is random.

Recessive Disease

Suppose both the father and the mother don’t have PFIC but both carry a mutation on one of their two copies of a gene related to a PFIC subtype (i.e. both parents are carriers). There is a 50:50 chance that a sperm or egg will have a defective copy of the PFIC gene. If both the egg and sperm have the defective copy of the PFIC gene, the resulting embryo (offspring) will have two copies of the defective PFIC gene and the offspring will likely have PFIC disease. For parents who are both carriers for a recessive disease their offspring have a 25% chance of being affected by the disease, while 50% of the offspring will be carriers and 25% will inherit two normal copies of the gene and be entirely unaffected. Note – if only one parent is a carrier and the other parent is unaffected, their offspring will have a 50% chance of being a carrier or 50% chance of being entirely unaffected.

Dominant Disease

If either the mother or father have PFIC on the basis of a dominant disease – their egg or sperm will have a 50% chance of having a defective copy of the PFIC gene. If either the egg or sperm carries the defective copy of the PFIC gene, the offspring will likely have PFIC disease. If one parent has the disease as a dominant disease, there is a 50% risk that their offspring will have the disease. This is independent of the status of the other parent.

Not all circumstances of PFIC follow these patterns exactly – as the type of mutation may impact the clinical features of the disease. There can be a spectrum of types of mutations from mild to severe and as such the severity of PFIC, even for a given subtype, can be variable. In addition, other genes and environmental factors may influence the severity of the PFIC disease.


PFIC Subtypes: Single Gene Mutations

rn rnrnAll PFIC subtypes are cause by a single gene mutation. The different PFIC Subtypes are related to different genes. In addition, not all mutations that cause a specific subtype are the same. In fact, researchers have found quite a few different mutations in each of the genes that are involved in the different subtypes. The genes related to the different PFIC subtypes have different functions, but they have in common that their malfunction causes cholestatic liver disease. The attached table was developed and generously contributed by Dr. Laura Bull and Dr. Richard Thompson.

Genetics of PFIC: Current Status and Implications

By Laura Bull, Ph.D. Professor Liver Center Laboratory, Department of Medicine, and Institute for Human Genetics University of California San Francisco. The attached paper was written by Dr. Laura Bull, PhD to provide and overview of the current understanding of the genetics of PFIC. This paper was updated in 2018. She will be working on an update based on the most recent findings to be available in January, 2021.