Information for Clinicians

Cystic Fibrosis (CF) is an autosomal recessive condition (https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/autosomal-recessive-inheritance/) with an estimated prevalence of ~1 in 3,000.  The most common associated complications are chronic lung disease, exocrine pancreatic insufficiency and male infertility.  It is estimated that ~1 in 20 to 1 in 25 of us are carriers of CF.  Being a carrier of CF is not expected to have any implications for your health, but it may have reproductive implications if both partners are found to carry CF variants.

Referral to Clinical Genetics:

We no longer see patients for CF carrier testing in the genetics clinic, unless there are additional concerns.  A couple who are both carriers of CF can be referred to Clinical Genetics if they are family planning and would like to discuss reproductive risks and options (e.g. preimplantation genetic testing and prenatal testing). If a patient has a family history of CF and is pregnant, they should be referred to Clinical Genetics to review their options.

Requesting CF Carrier Testing:

Non-genetic specialists (including GPs) can request CF carrier testing (5-10ml EDTA sample, sent to the Genetics lab).  It is imperative to state the name and details of the patient’s known affected relative. Further information on how to arrange carrier testing and interpretation of results can be found in this document – Cystic Fibrosis information sheet for GPs (link) or in the Scottish Genomic test directory ( NSD611-003.20-SSNGM-Test-Directory-Rare-Inherited-Disease-V5.pdf)

Genetic test request form can be found here: https://www.nhsggc.scot/downloads/routine-genetic-testing-request-form-2/. Alternatively, testing can be requested on Trakcare in ‘Lab – Adult’ using the request item ‘Germline molecular genetic analysis or storage’. Within the request, for ‘Testing Required’, select ‘Cystic Fibrosis/CFTR related condition’.  If ordering electronically please make sure to include the information about the relative known to be affected/a carrier as outlined above, as well as our reference/pedigree number if known.

Haemoglobinopathies are a group of inherited blood conditions caused by alterations in the genes that produce haemoglobin. Haemoglobin is the substance inside our red blood cells which picks up oxygen as blood passes through the lungs and carries it to the rest of the body. How an individual is affected by a haemoglobinopathy condition can vary, with some conditions causes mild to moderate anaemia and others causing significant health issues, such as sickle cell anaemia and beta thalassemia major. Typically haemoglobinopathies are inherited in an autosomal recessive pattern (https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/autosomal-recessive-inheritance/). Carriers of alterations in the haemoglobin genes are typically well and do not experience and health problems because of being a carrier.

Genetics clinic referrals:

We no longer see carriers of haemoglobinopathies in the genetics clinic, unless a couple are both carriers of a haemoglobinopathy and are family planning. These couples can be referred to Clinical Genetics to review their reproductive risks and options.

Requesting haemoglobinopathy screening:

Non-genetic specialists (including GPs) can request a haemoglobinopathy screen which is a haematological blood test that can determine haemoglobinopathy carrier status. Testing can be requested via TrakCare and a 4ml EDTA (purple topped) sample should be collected.

If a patient is found to be a carrier of a haemoglobinopathy condition and they are considering pregnancy testing should also be arranged for their partner. As above, carrier couples can be referred to Clinical Genetics.

Further information about haemoglobinopathies can be found at – https://www.gov.uk/government/publications/handbook-for-sickle-cell-and-thalassaemia-screening/understanding-haemoglobinopathies.

We do not routinely see patients for Haemochromatosis diagnostic or carrier testing in the genetics clinic, unless there are additional concerns.  Further useful information about the condition can be found via the NHS Conditions website: Haemochromatosis – NHS (www.nhs.uk)

Requesting genetic testing:

Non-genetic specialists (including GPs) can request haemochromatosis carrier testing (5-10ml EDTA sample, sent to Laboratory Genetics). Guidance for testing and management of Haemochromatosis have been produced by the British Society for Haematology (BSH).

Acceptance criteria must be met and stated on the request form (see  The Scottish Genomic test directory, NSD611-003.20-SSNGM-Test-Directory-Rare-Inherited-Disease-V5.pdf)

Genetic test request form can be found here: https://www.nhsggc.scot/downloads/routine-genetic-testing-request-form-2/

*Before requesting this test, please check clinical portal to ensure that the patient has not been tested before. The results of these genetic tests will not change over time, and so repetition is of no value.

Non-healthcare professionals are not permitted to request genetic testing.

Haemochromatosis is a common inherited condition that affects how the body absorbs iron from your diet. It is more common in those with Northern European ancestry. 

Individuals with hereditary haemochromatosis experience a slow build-up of iron in the body over a number of years. Too much iron in the body is known as iron overload.  The excess iron can be stored in organs and tissues and lead to symptoms such as fatigue, joint pain, abdominal pain, shortness of breath and weight loss.  The condition can also affect the organs in the body such as the pancreas and the liver, which can lead to diabetes, liver cirrhosis, arthritis, cardiac problems and skin discolouration.

Treatments can include iron monitoring, chelation therapy, venesection to remove blood and reduce iron levels and changes to diet and lifestyle.

The genetics of Hereditary Haemochromatosis

Haemochromatosis is caused by variants in a gene called HFE gene.  We all have two copies of this gene as we inherit one from each of our parents.  For an individual to be affected with hereditary haemochromatosis, they must have alterations on both copies of the HFE gene. Carriers have an alteration on only one of their copies of the HFE gene. Therefore, for an individual to be affected by the condition, both parents must be carriers.

When both parents are carriers of Hereditary Haemochromatosis, in every pregnancy there is a:

• 1 in 4 (25%) chance of having a baby who is not affected and not a carrier
• 2 in 4 (50%) chance of having a baby who is a healthy carrier
• 1 in 4 (25%) chance of having a baby who is affected by the condition

This is known as autosomal recessive inheritance.

Genetic testing for Hereditary Haemochromatosis 

Individuals who meet the testing criteria outlined the Scottish Genomic test directory (link can be found on the website) or who have a first-degree family member who is known to carry an HFE variant can have genetic testing arranged by non-genetics specialists (including GPs). Testing requires a 5-10ml EDTA sample sent to Laboratory Genetics with a genetic test request form (see website for link). Testing covers common alterations C282Y and H63D.

Genetic test results interpretation

No Variants detected

If a patient’s results showed they do not have the C282Y or H63D alterations in the HFE gene they are not likely to have hereditary haemochromatosis. We would not offer any further genetic testing or clinical follow up. If an individual is experiencing iron overload symptoms they should be investigated and treated as appropriate, but these are not likely to be caused by hereditary haemochromatosis.

Heterozygous for C282Y or H63D

If a patient has been found to be a carrier of HFE-related haemochromatosis they have an alteration on one copy of their HFE gene. Carriers of the condition are generally well and are unaffected with the condition. To be affected an individual must have genetic alterations on both their copies of the HFE gene, which leads to iron overload.

As carriers are generally well, they do not require any treatment or follow up therefore there is no further genetic testing that we would offer to your patient. If an individual is experiencing iron overload symptoms they should be investigated and treated as appropriate. However, these symptoms are not likely to be caused by HFE-carrier status.

Homozygous C282Y

Individuals who are found to be homozygous for the C282Y alteration in the HFE gene are generally affected by haemochromatosis and experience iron overload. Symptoms can be variable but generally include fatigue, joint paint, abdominal pain and weight loss. If left untreated it can lead to worsening symptoms including liver disease and diabetes. If an individual has raised iron levels, they should be referred to gastroenterology for management and follow up (see full management guidelines via link on website).

Compound Heterozygous C282Y/H63D

Individuals who are found to be compound heterozygous for the C282Y and H63D alterations in the HFE gene can experience iron overload. However, iron overload in these individuals happens at a slower rate than those homozygous for C282Y. Individuals can experience symptoms but are at a lower risk of serious complications such as organ failure. If ferritin and transferrin saturations levels are normal it is recommended that individuals have these check every 3 years. This can be done through the GP. If levels are raised individuals should be referred to Gastroenterology for management and follow up. 

Homozygous H63D

Individuals who are found to be homozygous for the H63D alteration in the HFE gene are unlikely to experience iron overload. Some individuals can experience iron overload and should have any symptoms investigated. This result does not confirm or exclude a diagnosis of haemochromatosis. If homozygous individuals do not have a raised iron level regular iron monitoring is not required. Genetic testing is not recommended for family members of homozygous individuals who do not have symptoms.

Implications for children

Testing Children – Carriers

If a patient is a carrier of haemochromatosis (heterozygous for H63D or C282Y) any children have a 1 in 2 (50%) chance of also being a carrier. Genetic testing can be carried out from the age of 16 via the GP practice. As mentioned, Carriers are generally well and do not experience any symptoms. If both parents are carriers there is a 1 in 4 (25%) chance any children will be affected. If any children are found to be affected, they should be referred to gastroenterology for follow up and management.

Testing Children – Affected

If a patient is affected with haemochromatosis any children that they have will be a carrier of the condition. This is because affected individuals have alterations in both copies of their HFE gene. We always pass on one copy of each of our genes to our children, so children of affected individuals will always inherit an altered copy of the HFE gene making them a carrier of haemochromatosis. If an affected individual’s partner is a carrier of haemochromatosis there is a 1 in 2 (50%) chance any children will be affected with the condition. Children can be tested from the age of 16 through their GP practice. If they are found to be affected, they should be referred to gastroenterology for management and follow up.

Implications for first degree family members

Parents and siblings of individuals who are carriers or affected by Hereditary Haemochromatosis can request genetic testing via their GP to clarify their carrier status. Partners of individuals who are affected or carriers can also seek testing via the GP. Results interpretation and management guidance as above.

Reproductive implications

If an individual is affected with Hereditary Haemochromatosis and their partner is a carrier, there is a 1 in 2 chance any children they have will be affected by the condition. If their partner is not a carrier any children, they have will all be carriers of the condition. Since Hereditary Haemochromatosis is an adult-onset condition with a number of management options genetic testing during pregnancy (prenatal testing) is unlikely to be offered. See above section about testing children.

If a couple are both carriers of Hereditary Haemochromatosis any children have a 1 in 4 chance of being affected and a 1 in 2 chance of being a carrier. As above prenatal testing is unlikely to be offered, and children can consider testing from the age of 16 via their GP.

Patient resources

Further information for patients can be found at the following links:

• Haemochromatosis UK – https://www.haemochromatosis.org.uk/
• NHS Inform – https://www.nhs.uk/conditions/haemochromatosis/
• Kings Collage Hospital NHS Foundation Trust – https://www.kch.nhs.uk/wp-content/uploads/2023/02/2952-Genetic-Haemochromatosis-v7.pdf