Reproductive carrier screening to avoid recessive disease in the Scottish islands

Professor Jim Flett Wilson writes:

At least 4,000 diseases of this sort are known, all of them rare. In large cosmopolitan populations, these variants are very rare, so the chances of a man marrying a woman with a variant in the same gene are miniscule. That is, unless you are related to your spouse, for example by being cousins, because we share DNA with our cousins. That increases the chances that both you and your spouse carry the same disease-causing variant, and hence a child could inherit two copies of the variant, causing disease.

However, in isolated populations, such as Orkney, Shetland, the Hebrides and the Jewish community, things are different, because the frequency of the variant can be so high that it doesn’t matter if you marry your cousin or not, the risks are similar. The rise in frequency is nothing to do with cousin marriage, it is rather because of a lack of dilution by immigrants over the centuries in small communities. In these situations, very many people descend from a small number of founder ancestors, and if one of these ancestors happened to carry a disease-causing variant, then a considerable number of his or her descendants can carry that variant today. 

One way of thinking about it is that instead of there only being a risk when marrying your first or second cousin, the risk arises if members of numerous large kindreds – that is groups of a few hundred descendants of a couple born circa 1800 – intermarry with one another. For the conditions I have studied in each of Orkney, Shetland and the Hebrides, there are ten to twenty of these large kindreds for each disease, where half the members in each succeeding generation are carriers. For instance, a carrier from kindred A could marry a carrier from kindred B and go on to have a child with the disease in question, despite not being related through paper-based genealogy. Because of the large numbers, the chance of marriage among these kindreds is much higher than that of marrying one of your much smaller number of cousins, even before considering that cousin marriage is not a norm in the Scottish islands today. Therefore, the risk is much higher in Scottish island communities, even in the absence of inbreeding: unbeknown to them, a considerable number of couples in the community are at risk of having children with the disease. 

For example, 1 in 45 people with four Shetlander grandparents carry a variant causing Batten disease, a fatal neurodegenerative disease of childhood, where the baby is often floppy and can go blind. Carriers are spread the length and breadth of the islands, from Dunrossness to Yell and Waas to da Skerries, in about twenty large kindreds.

Hence, many couples where both partners are from Shetland could be at risk of bringing a Batten baby into the world. Indeed, carrier couples are running a one-in-four chance for each child they have. This is why these diseases tend to cluster among brothers and sisters. If one affected child is born, it shows that both parents are carriers and thus there is a significant chance of further children being born with the condition. This was more obvious long ago, when people tended to have larger families. 

Other recessive diseases with a higher risk in Shetland include the intellectual disability Cohen syndrome, the copper overload disorder Wilson disease and the blood abnormality sitosterolaemia, where the body absorbs too much fat from plants, leading to increased risk of heart disease. Sitosterolaemia is also found in the Outer Hebrides, but is treatable with dietary changes and medicine. 

One of the increased risks in Orkney is for the pigment and vision disorder, albinism. As well as poor eyesight such as short-sightedness, albinos often experience sensitivity to light, involuntary eye movements or a squint, resulting in low vision which cannot be corrected. At least six albinos are known historically from the West Mainland of Orkney. However, the variant is spread across more than ten large kindreds, thoughout the archipelago, from Harray to Hoy and Westray to South Ronaldsay. About 1/100 Orcadians are carriers.

The iron-overload disorder, haemochromatosis – also known as the Celtic curse – is the most common recessive disease of all, and increases the risk of liver cancer, fibrosis, cirrhosis, arthritis and joint replacement. It is particularly concentrated in the Outer Hebrides and Skye, where about one quarter of people are unaffected carriers, and one in sixty have two copies of the variant and thus are likely to go on to develop the disease. The high risk is found in Barra, Uist, Harris and all parts of Lewis, as well as in Skye.

Despite having lower frequencies, haemochromatosis is still the most common carrier condition in both Orkney and Shetland as well, where about one ninth of the population are carriers. Scottish or Irish immigrants to the Northern Isles have higher carrier frequencies.

The life-limiting lung disease, cystic fibrosis (CF) is also more frequent across Scotland: about 1/25 to 1/30 people carry the most common disease-causing variant, whether on the Scottish mainland or the islands. 

Unlike CF, which is also common in Mainland Scotland, the risks of all the other rare, island-specific diseases decrease for families with only partial ancestry from the islands, for instance to half the risk for those with two grandparents from one of the archipelagos. In many cases there is no known family history of the disease; it can skip generations, exactly like red hair.

It is clear that each community has its own set of risks, just as some Jewish groups have a high risk of Tay-Sachs disease. Indeed, the charity J-netics now screens for 47 different recessive diseases in the Jewish community. The Scottish islands likewise appear to be enriched for further variants not mentioned here; we are only just scratching the surface.

There is therefore a need for screening for recessive conditions in the Scottish islands – called reproductive carrier screening. This would be a step towards a preventative model of healthcare, where the risks are predicted ahead of time.

Ideally, reproductive carrier screening is carried out before a couple starts a family, either for each individual separately, or as a couple. If only one partner carries the variant causing a given condition, then there is no risk of disease in the children, just as when neither partner carries a variant. Only when both partners carry a variant in the same gene are the children at risk. 

In this case, genetic counsellors would help decide the way forward, which will depend on individual choice and the particular disease. For treatable diseases, like haemochromatosis, sitosterolaemia and Wilson disease, for instance, genetic testing could be targeted to the babies in these families. Being discovered early will allow them to take up the recommended pathway of care, which may involve medication, dietary changes, or involve blood tests at the appropriate point(s) in life. 

For untreatable, fatal or life-limiting diseases, such as Batten disease, options include diagnostic testing during pregnancy, having IVF (in vitro fertilisation) followed by pre-implantation genetic testing in order to select unaffected embryos, or using IVF with donor sperm or eggs. This kind of carrier screening would help those who need it to make informed reproductive choices, and bring valuable peace of mind to everyone else. Understanding which variants you carry could be important to share with members of your family, whatever age you might be, for instance if they have not been screened or live away and cannot access this testing.

Carrier screening differs from the traditional newborn Guthrie heel prick test, which now tests for 11 conditions, including cystic fibrosis, but none of the other diseases mentioned here, after the baby is born. In a related vein, NHS England’s Generation Study is now sequencing the whole genomes (reading all the DNA) of 100,000 newborn babies in England, testing for over 200 conditions. While this is laudable, it is also very expensive, and raises the question of why the millions of us who are already alive cannot easily get screened? 

Viking Genes already plans to screen 5000 willing adults in each of Shetland and the Hebrides for actionable variants, once funding has been secured. Actionable variants differ from carrier variants, as they typically cause disease when only one copy is present, and all are treatable; you can take action to prevent the disease. Examples include the famous BRCA2 variant causing breast, ovarian and prostate cancer, or the variant causing inherited high cholesterol and heart attacks. The risk of actionable variants was lower in Orkney, hence priority has been given to the other islands. 

It seems clear that added value for money would come from combining the proposed actionable variant screening with reproductive carrier screening in a “one-stop shop”.  The governance, laboratory and IT costs would all be shared. That is why we are planning to deliver both actionable and carrier screening in each of the Shetland Community Screening Project and the Hebrides Community Screening Project. 

The various reproductive carrier screening programmes among Jewish communities over the last 30 years have led to a significant drop in the frequency of Tay-Sachs disease, to the point that it is now more prevalent in non-Jewish families. Let us use genetic screening to reduce the risk to our islander children and prevent the unnecessary suffering brought about by scourges such as Batten disease.