Patients who are UNLIKELY to benefit from a referral to Clinical Genetics

Alpha-1 antitrypsin deficiency (AATD) is one of the most common metabolic disorders in people of northern European heritage, with an estimated prevalence of ~1 in 2,000 – 5,000.  The most common associated complications are chronic lung disease (e.g. emphysema and bronchiectasis) and liver dysfunction.  AATD is an autosomal recessive disorder.  It is estimated that ~1 in 20 of us are carriers of AATD.  Carriers of AATD are not expected to be at an increased risk of liver or lung disease.

We do not see these patients in the Genetics clinic, unless there are additional issues.

Non-genetic specialists (including GPs) can request testing for AATD (4ml gold top blood sample, sent directly to Clinical Biochemistry).  See also the Belfast Trust Laboratories User Manual

* Before requesting this test, please check ECR 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.

• GOSH A1ATD patient information leaflet
• A1ATD factsheet for primary care
• ADAPT Partial A1ATD (Pi MZ) information leaflet

For more detailed information on CF and understanding results please see here.

Cystic fibrosis (CF) has an estimated prevalence of ~1 in 3,000.  The most common associated complications are chronic lung disease, exocrine pancreatic insufficiency and male infertility.  CF is an autosomal recessive disorder.  It is estimated that ~1 in 20 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.

We do not see patients for CF carrier testing in the Genetics clinic, unless there are additional issues.  Where both partners are found to be carriers of CF, the couple can be referred to Clinical Genetics to discuss reproductive options (e.g. preimplantation genetic testing, PGT).

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. Click here for the Test request form.

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

Non-genetic specialists (including GPs) can request haemochromatosis carrier testing (5-10ml EDTA sample, sent to the Genetics lab).

Acceptance criteria must be met and stated on the request form (see BSH guidance and NHS England Genomic Test Directory Eligibility Criteria).

Click here to download the test request form.

*Before requesting this test, please check ECR 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.

For patients identified as homozygous for C282Y or compound heterozygous for C282Y/H63D, further advice is available from local gastroenterology services, or Hepatology at RVH (if a Belfast Trust Area patient).

The Winton Centre for Risk and Evidence Communication provide some useful letter templates / patient information leaflets on various Haemochromatosis (HFE) results.

FASD standard letter

We do not routinely see patients with suspected fetal alcohol spectrum disorder (a.k.a fetal alcohol syndrome) in the Genetics clinic.  There is no genetic test available to confirm, or refute, a diagnosis of fetal alcohol spectrum disorder.  We recommend referring to the Scottish Intercollegiate Guidelines Network (SIGN) 156 guidelines ‘Children and young people exposed prenatally to alcohol’.

Following your assessment, if you suspect that the patient has an alternative dysmorphic syndrome, please feel free to refer to Clinical Genetics, or to contact us for discussion.  Ideally, a chromosome analysis by microarray should be sent prior to referral. Click here for the test request form.

If you would like the support of Clinical Genetics in assessing for the sentinel facial features of fetal alcohol syndrome please feel free to e-mail photographs of the patient to genetic.medicine@belfasttrust.hscni.net (you must have the consent of the patient/ guardian).

We do not see patients for MTHFR testing in clinic, or to assist in the interpretation of private MTHFR testing results.

The MTHFR gene encodes an enzyme which converts homocysteine to methionine.   Genetic variations in MTHFR can lead to impaired function of this enzyme, which may result in mild increased homocysteine levels, particularly in individuals who are folate deficient. However, the health implications of this remain unclear.

There are some variants/’polymorphisms’ in MTHFR which are commonly found in the general population.  It is estimated that ~10% of individuals in the UK & Ireland are homozygous for the C667T variant (“TT homozygous”).  A1298C is another commonly observed MTHFR polymorphism.

There have been many studies exploring the relationship between MTHFR variants and a multitude of health disorders.  Among C677T homozygotes, who have demonstrable elevation in homocysteine levels, there may be a slightly increased risk of venous thrombosis and recurrent pregnancy loss.  However, the absolute risk increase is small, and the American College of Medical Genetics (ACMG) currently do NOT recommend MTHFR testing as part of the clinical evaluation of thrombophilia or recurrent pregnancy loss.

Some studies have also suggested that women who are C677T homozygotes are at increased risk of having a child with a neural tube defect, particularly if the baby is also a C667T homozygote.  However, again, the absolute increase is small. At present, pregnant women who carry the variants described are recommended to take the standard dose of folic acid (in the absence of any other indication for high dose folic acid).  Substituting with other folates, such as 5-MTHF, is NOT recommended.

Overall, we would reassure patients who carry these common variants that this is extremely common in the general population, and based on the scientific evidence currently available, we would not expect this to have significant implications for their health.  Furthermore, we would not recommend any specific treatments or supplements.

Please note that these common MTHFR variants/polymorphisms would not be associated with very high homocysteine levels.  If your patient has very high homocysteine levels and/or other features suggestive of Homocystinuria, then they may need referral to an appropriate specialty (e.g. Clinical Biochemistry).

We do not routinely see patients with an isolated neural tube defect in the Genetics clinic.  However, if there are additional features which might suggest an underlying genetic syndrome, or a family history of close relatives who are affected with a neural tube defect, then referral to Clinical Genetics may be appropriate.

Neural tube defects, information for clinicians

Nureal tube defects, information for patients/parents

Women who have had a previous pregnancy affected by a neural tube defect, or have a family history of a neural tube defect, are advised to take high dose folic acid (5mg), which can be prescribed by their GP.  This can significantly reduce the chance of having another baby with a neural tube defect.

For further information on neural tube defects, including recurrence risks, please see this information leaflet.

Type 3 EDS standard letter

We do not see patients with suspected Hypermobility Spectrum Disorder (a.k.a Joint Hypermobility Syndrome/ Hypermobile Ehlers-Danlos Syndrome/ Ehlers Danlos Syndrome type 3) in the Genetics clinic.

Hypermobility Spectrum Disorder is a clinical diagnosis, and there are no genetic tests available to confirm the diagnosis.  For further information please see: Joint hypermobility syndrome – NHS

Referral to an appropriate specialist (e.g. Paediatrics, Physiotherapy) for assessment or supportive management may be required. 

If you feel your patient may have additional features, suggestive of a different genetic connective tissue disorder (see standard letter above for examples), then please feel free to refer the patient or to contact us to discuss.

We do not routinely see patients with autism in the Genetics clinic, unless there are additional features, or a significant family history.  There is no genetic test to diagnose autism.

The genetics of autism remains poorly understood, and it is hypothesised that autism results from a complex interaction of polygenic and environmental factors.  It is not unusual to see several individuals with autism in one family.  Studies have suggested that parents who have one child affected with autism, are more likely to have another affected with autism (~18% recurrence risk).  The recurrence risk is higher if there are multiple affected siblings, and for male offspring.

If you feel that the patient has additional features to suggest an underlying syndromic diagnosis, please feel free to refer, or to get in touch to discuss. If there are additional features to warrant a referral then a chromosome analysis by microarray should be undertaken prior to, or at the same time as, the referral. Click here for the test request form.

GeNotes have produced some information on the genetics of autism, aimed at health professionals.

Inherited cardiac conditions (including hypertrophic cardiomyopathy, dilated cardiomyopathy, long QT syndrome, Brugada syndrome, CPVT) are usually managed by local Cardiology departments, and/or the Inherited Cardiac Condition Service at Belfast City Hospital.

Patients with a suspected aortopathy (e.g. Marfan Syndrome) should be referred to the Clinical Genetics service.

Inherited hyperlipidaemia disorders (e.g. familial hypercholesterolemia) are usually managed by local Cardiology departments and Lipid clinics.  Cascade testing, of at risk relatives, is usually undertaken by nurse specialists based within each Trust.

Inherited haematological conditions (e.g. haemophilia, thalassaemia, sickle cell disease) are usually managed by local Haematology departments, and/or the tertiary Haematology service at RBHSC (children) or Belfast City Hospital (adults).

Direct to consumer (DTC) genetic testing refers to genetic testing provided by a commercial laboratory, without the requirement for a consultation with a health professional.  It is typically procured by healthy individuals.

Different commercial companies will use different genetic testing methodologies.  The laboratories providing DTC testing may not be under the same regulations as those providing testing for recognised health services.  Several companies use a “SNP chip” based methodology.  Reportedly, this methodology has a high rate of false positives and artefacts.  Furthermore, as many companies limit the variants that they test for (e.g. Ashkenazi Jewish founder variants in BRCA1/2) a normal result may provide false reassurance.  The quality of pre and post-test support for consumers also varies.

The Royal College of General Practitioners & The British Society for Genetic Medicine have a joint position statement on DTC: Position Statement on Direct to Consumer Genomic Testing | RCGP & BSGM

At present, we do not routinely see patients to discuss the results of DTC testing, however if you are unsure, or wish to discuss, please feel free to contact us.

Patients with a relevant family history (see also  Common referrals) can be referred to our services the usual way (How to make a referral to Clinical Genetics section).

Other useful sources of information on DTC genetic testing:

• Association of Genetic Nurses and Counsellors (AGNC) information leaflets for patients: Documents & Websites – AGNC
• Genomics Education Programme (Jan 2020) Direct-to-consumer testing: a clinician’s guide Direct-to-consumer testing: a clinician’s guide – Genomics Education Programme (hee.nhs.uk)
• Horton, R et al. (2019). Direct-to-consumer genetic testing. BMJ 367: l5688.
• Weedon, M et al. (2019). Very rare pathogenic genetic variants detected by SNP-chips are usually false positives: implications for direct-to-consumer genetic testing. BioRxiv, 10, 696799.
• House of Commons Science and Technology Committee (Nov 2021) Direct-to-consumer genomic testing: Government Response to the Committee’s First Report. Government Response to the House of Commons Science and Technology Committee’s Report on Direct-to-Consumer Genomic Testing (parliament.uk) (see Recommendation eleven)

Please see here for more information and a parent information leaflet.

We do not routinely see couples who have had a pregnancy or child affected with a “common” trisomy (Down Syndrome, Edwards Syndrome, Patau Syndrome) in the genetics clinic.