Genetics

Mostly PCD occurs when both parents of a child are carriers of the condition. In these cases, two copies of the faulty gene are needed to cause the condition. A carrier of a condition has just one copy of a faulty gene. They will usually be unaffected and will therefore not know that they are at risk of having an affected child.

The second way to inherit PCD is when the mutated gene is on the X chromosome so PCD is passed down from the mother. The faulty PCD gene can cause the cilia not to work properly e.g. they may move too fast, too slow, are completely static or are completely missing. Each different gene can cause different type of issues for the PCD patient e.g. some people have really bad sinusitis but good lungs, others have poor lungs and situs inversus. This area of research is still being expanded on all the time to better understand the disease.

Currently in the UK, diagnostic testing can only identify the gene causing a person’s PCD in up to 70% of PCD cases.  To be diagnosed with PCD then you will need to have a combination of tests including nasal biopsy and sometimes genetic tests.  Please see our diagnosis page for more information.

DNA is a type of chemical called a nucleic acid. DNA stands for deoxyribonucleic acid. All of the DNA in your cell, when considered together, is called your genome. Your genome does not consist of one single long DNA molecule, but rather 46 long DNA molecules called chromosomes. You have 23 pairs of chromosomes: one set from your mum and one set from your dad. Along these chromosomes are subunits called genes, which provide a code for making short sections of another type of nucleic acid called RNA. Whereas DNA is a very long-lasting storage molecule which is passed down from generation to generation to generation over millions of years, these RNA molecules are very short-lived templates. RNA is a template for making proteins. Proteins are the building blocks of your cells. For example, one gene will code for an RNA molecule, which will code for a protein such as one of the ‘radial spoke proteins’ which make up part of the cilia in your airways.

Your genome is like a recipe book; with each gene in the genome being like a word in the recipe book. Just as a word in a recipe book tells you which ingredients to mix to make a cake, each gene tells your cells which proteins to make to produce a cilium or other structure in your body.

Just like the words in the recipe book, genes are made up of letters too. Each strand of DNA is formed of four basic building blocks or ‘bases’: adenine (A), cytosine (C), guanine (G) and thymine (T). Sometimes the letters can get swapped, or letters can get added or deleted. This can mean that the code does not make sense anymore, and we make the wrong protein or no protein at all. It is a bit like the letters of your recipe book getting swapped so that you put HAM in the middle of your cake instead of JAM. Just a small 1 letter difference can have a very big effect on how you make your cake. Similarly, just a single letter change in your DNA can have a big impact in how you make a protein, so that your cells and your body work quite differently.

Genes are sections of DNA that contain the set of instructions to produce one specific molecule in your body; RNA, which usually makes a protein. These proteins control how our body grows and works; they are also responsible for many of our characteristics, such as our eye colour, blood type or height.

The human genome contains around 20,687 protein-coding genes. Different genes or instructions are read at different times in different cells in response to the requirements of our bodies. Each cell contains two sets of genes, one from your mother and one from your father. For ease of storage and access, the genes are packaged up into 46 parcels called chromosomes.

Chromosomes are bundles of tightly coiled DNA located within the nucleus of almost every cell in our body. Humans have 46 chromosomes in their somatic (non-reproductive) cells. We inherit one set of 23 chromosomes from our mother and one set of 23 chromosomes from our father. So we have two sets of 23 chromosomes or 23 pairs.

Mutations can occur as a natural consequence of errors in DNA replication or due to exposure to chemicals or radiation (e.g. UV) which cause the DNA to mutate.  They disrupt normal gene activity and cause PCD because the gene is not carrying the correct instructions to the body.

PCD occurs only when both parents of a child are carriers of the condition. Two copies of the faulty gene are needed to cause the condition. A carrier of a condition has just one copy of a faulty gene. They will usually be unaffected and will therefore not know that they are at risk of having an affected child. A PCD diagnosis normally ‘comes out of the blue’ to families. It is only once a couple have had one affected child that they discover they are at risk of having more affected children. They will have a 25% (one in four) chance of having a child affected by this condition. Additionally, there is a 50% (two in four) chance that their child will be an unaffected carrier.

There are at least 2 ‘X-linked’ forms of PCD (i.e. the mutated gene is on the X chromosome). These are caused by mutations in genes PIH1D3 and RPGR which are on the X chromosome.

These are inherited differently because females have two X chromosomes and males have an X and a Y chromosome.

Because males do not have a second X chromosome, they only need to inherit 1 copy of mutant PIH1D3 or RPGR to develop PCD. They will always inherit this from their mother, because they always get the Y chromosome from their father.

Extra information can be found on these sites:

Genetic causes of PCD

Finding out about genomics from the Genomics England

Learning about genetics from Genetic Alliance UK

DNA: The genetic code that determines all the characteristics of a living things. It is like an ‘instruction book‘ to determine what we look like and how we function. ‘Spelling mistakes’ (known as ‘mutations’, see below) within the code can cause PCD.

Gene: A unit of DNA that controls the development of one or more characteristics such as eye/ hair colour or how our cilia work.

Genetics: The study of genes and how they are inherited. In relation to PCD, genetics is usually describing the test or result which finds the gene responsible for causing PCD. We only know about approximately two thirds of PCD causing genes which means a negative result does not mean you don’t have PCD, although does make this less likely. 

Heterozygous: Having 2 different versions of the same instructions within a gene e.g. one PCD mutation and one healthy copy, therefore not causing PCD. This is also sometimes described as you being a ‘carrier’ for a PCD mutation.

Compound heterozygous: Having 2 different mutations or ‘spelling mistakes’ within the same PCD gene. If both of these ‘spelling mistakes’ are ‘pathogenic’ (see below) then this will be the cause of you having PCD 

Homozygous: The inheritance of 2 of the same mutations or ‘spelling mistakes’ within the same gene. If pathogenic, these ‘spelling mistakes’ would cause PCD. 

Mutation: If we think of our DNA as an instruction book, a mutation within a gene is like a ‘spelling mistake’. Some of these mutations cause no issues whilst others can cause genetic conditions such as PCD. You normally need to inherit a mutation from both parents to have PCD. 

Pathogenic: Disease causing. In this case a pathogenic mutation or ‘spelling mistake’ which is known to cause PCD. 

Phenotype: Characteristics seen in an individual with a genetic cause. This can be clinical characteristics e.g. wet cough or microscopic characteristics e.g. static cilia

RNA sequencing: A special test occasionally undertaken when a genetic result is uncertain. It is used as a research tool to help understand whether a mutation, which is not fully understood, causes a problem. If you or your child needs this, further explanation will be given by your team.  This is not a standard diagnostic test and is only carried out through research funding when available.

Variant of unknown significance (VUS): A mutation or ‘spelling mistake’ which can be seen but it is unknown whether it causes a problem. Some patients may have one pathogenic mutation and one VUS which would mean we wouldn’t know for sure they had PCD without other test results to confirm a diagnosis. 

Whole exome sequencing: A special test occasionally undertaken when a genetic cause is unknown. This is not a standard diagnostic test and is normally only carried out through research funding when available.

Whole genome sequencing: Some patients have taken part of the100k genome project which looked at their whole genome (their whole genetic ‘instruction manual’). Most PCD genetic testing looks at specifically at known PCD causing genes. Whole genome testing looks more widely and may identify further PCD genes in the future. The project is closed to new recruits, but it is still a term you may see, and may be available on a research basis in some centres.