Background

A patient tells you he/she (or his/her partner) has a relative with cystic fibrosis (CF). As CF is so common in Ireland, we do offer carrier testing if there is a family history. However, whilst parents of a child with CF have a one in four risk of recurrence, more distant relatives overall have a <1% chance of having an affected child, unless their partner also has a family history.

Prior to testing, the risks to relatives are detailed in the table below.

What Can You Do?

• Offer genetic testing, if the person so wishes.
• Carrier testing is available to anyone over the age of 16 who has a relative or partner who has CF or carries a CF mutation.

What Type of Blood Sample is Needed?

• A 2-3ml peripheral blood sample in an EDTA bottle is required.
• This is the same bottle used for full blood count (FBC) analysis.

Does the Blood Sample Need to be Refrigerated?

• If possible, please refrigerate the sample, however it should be fine at ambient temperature for several days.

What information needs to be included with the referral?

• Your patient’s name and date of birth
• The name and date of birth of the family member or partner who has CF or is a carrier of a CF mutation and their relationship to your patient*
• The ethnic background of the patient as different mutations are responsible for CF in different ethnic groups
• Your own contact details

* If the mutation in the affected relative is not known, testing can be done for common CF mutations. A report can be issued but it will contain a caveat and the result may not be as definitive as one would like.

How Do I Order a Test Form?

• Download a CF test request form
• Guidelines for packaging specimens

Background

A woman tells you she has a relative with an X-linked disorder and is worried about her risks of having an affected child

The risk to this lady depends on (i) the type of X-linked disorder, (ii) who the relative is and (iii) how she is related to them.

• If the relative is on the fathers side of the family (e.g. brother/cousin of her father), and her father is healthy then she is not at risk.
• If a woman’s father is affected by an X-linked condition then she is an obligate carrier of that disorder (e.g. haemophilia in a man means that all of his daughters will be carriers).

More Information

Background

This scenario describes a situation where a more distant family member (not the patient’s child) has Down syndrome. Parents of children with Down syndrome do have an increased risk above population and these families should be dealt with by the local maternity unit. The National Centre for Medical Genetics will see those families with high risk Down syndrome due to translocation.

A patient tells you he/she (or his/her partner) has a relative (not his/her own child) with Down syndrome. They wish to know whether they are at increased risk of having a child with Down syndrome.

Down syndrome can be caused by:

• Non-disjunction [47,XY +21 or 47,XX + 21], (95% of cases) where there is no increased risk to more distant relatives
• Translocations involving chromosome 21 (~3%), where the chromosome report clearly states this and recurrence risk can be increased for more distant family members
• Mosaic Down syndrome (~2%) where there is no increased risk to more distant family relatives

Translocation Down Syndrome

Chromosome laboratories alert clinicians looking after a child with a translocation form of Down syndrome of the increased risk. NCMG make a concerted effort of follow up these families. However, disclosure of personal information is only through the family so it is possible that an at-risk relative will not have been informed if communication within a family is difficult.

How to Deal with a Family History of Down syndrome

Attain the name of the affected relative so that NCMG can check if there is any record of that child on their system and advise you whether your patient is at risk or not. However, NCMG will not have the records of all cases of Down syndrome in Ireland as the laboratory only started in the 1990’s and many prenatal tests for Down syndrome are sent abroad.

What if there is no Record of the Relative’s Chromosome Report?

If your patient is particularly worried, they need to go back to the family of the affected relative and gain information on what type of Down syndrome their relative has. Without this information, accurate advice cannot be given. The approach to the family with the affected individual has to be through the individual concerned (not by the midwife/clinician/medical team).

Family History of Non-Disjunction Down Syndrome

Family History of Translocation Down Syndrome

Background

A patient tells you he/she (or his/her partner) has a relative with an intellectual disability (ID).

There are numerous causes of intellectual disability and it might not be possible to identify a cause. Many families have been given diagnoses in the past which are erroneous. The Clinical Genetics team can only give advice when a diagnosis is confirmed by medical notes (+/- laboratory test).

The closer the relationship to the individual with ID, the higher the risk that the couple may have an affected child.

Intellectual disability can be due to:

• non genetic causes, or
• genetic causes

The genetic causes can be due to a:

• chromosomal anomaly, or
• single gene anomaly

Both of these anomalies can occur as a sporadic event (new mutation) in a family with negligible recurrence risk to at-risk relatives. However, some inherited forms can occur (chromosomal translocations, X-linked genes causing ID in males etc), so there may be a risk to your patient.

Next Steps

NCMG advice in this scenario is to determine:

• who was affected in the family and how they are related to the couple in the antenatal clinic?
• was the affected individual(s) a male or female?

If your patient is concerned and you need advice, we will need details (name, date of birth) of the affected relative(s). We can then search to see if there are any records of the affected cases and outcomes would be as follows:

• If we could find no records- we cannot help. Depending on the pedigree structure we could give an estimate on recurrence risks (after weighing up all possible modes of inheritance)
• The records are found but indicate that no diagnosis had been reached. Depending on the pedigree structure we could give an estimate on recurrence risks (after weighing up all possible modes of inheritance). We might suggest more updated tests on the affected individual that could be offered, but this is only appropriate if your patient is the parent of an affected child. We cannot re-investigate other people’s children (to help establish their relative recurrence risk) without their consent.
• The records are found and NCMG is able to establish a diagnosis from the records. Under these circumstances, we would be able to give accurate risks to your patient. Ultimately, this could mean (1) Negligible risk to your patient; no tests required; reassure your patient, (2) increased risk established; NCMG will advise accordingly and arrange assessment

Background

Consanguinity refers to the occasions where a couple who are expecting a baby are related to each other. Consanguinity is practised in a lot of societies and ~ 20% of the worlds births are to consanguineous relationships.

There is an increased risk of autosomal recessive disorders occurring in consanguineous relationships. This occurs when both parents are carriers of a recessive gene which does them no harm as they have a normal copy of the gene to compensate. We all carry two copies of every gene. If the couple both pass the recessive gene onto their child, he/she will be affected.

Risk of Recessive Disorder to a Pregnancy Where Consanguinity Exists

What Should you do if a Patient Tells you he/she is Related to his/her Partner and They Wish to Have Children?

• Find out how they are related
• Find out if there are multiple consanguinity loops in the family (describes situation where relationship is more than just a once off cousin marriage- where cousin marriages have been occurring throughout the family tree- increasing the risk of autosomal recessive disorders)

How should one advise couples who are related to each other?

• This depends on the ethnicity of the couple
• If the couple are ethnically Irish we offer detailed antenatal ultrasound scans and Cystic fibrosis carrier testing
• If the couple are from the Irish Traveller population, there are distinct genetic disorders that are known (see table below)
• The Irish Traveller population are a group at high risk of having a child with an autosomal recessive disorder. We do welcome referrals into our service from this population as we can offer specific genetic testing which will help define the couple’s risk.

Disorders, Frequency and Testing

Below we have listed some of the disorders we find amongst the Irish Traveller population. In taking a family history you might consider asking specifically about whether any of these conditions are seen within their family.

If the couple are not ethnically Irish, we can offer targeted genetic testing depending on the ethnicity:

• Pakistani couple: offer Beta thalassemia carrier screen and detailed ultrasound scan
• Chinese couple: offer alpha thalassemia carrier screen and detailed ultrasound scan
• Couple from elsewhere- contact NCMG and we can advise accordingly

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