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Title

Effects of endogamy versus consanguinity on risk of rare disorders

Community 1

Community 2

Community 3

Lay summary

Couples who are closely related (e.g. in which the husband and wife are cousins) are at increased risk of having a child with a rare genetic disorder such as severe learning disability. Specifically, they are at higher risk of having a child with a so-called recessive disorder, in which one has to inherit a particular DNA change from both parents to be affected. Similarly, recessive disorders are also more common in the children of couples in which the husband and wife are not closely related but come from the same clan, caste or kinship group (such as a biraderi group, in the context of the Pakistani community). This is particularly the case if people from that group have been marrying within the group for many generations. One of the reasons for this is that sometimes a genetic change that causes a disease can become much more common in a small caste or biraderi group just by chance. 

We do not know the relative risks of having a child with a rare disorder that are conferred by marriages between cousins versus marriages between unrelated individuals from the same biraderi/caste. These risks are likely to be different between disorders and populations. We will examine this using genetic data from Genomics England and the Deciphering Developmental Disorders studies. We will initially focus on British Pakistanis since they are one of the largest ethnic minorities in the UK, and because in this community, it is common for people to marry their cousin or someone from the same biraderi group, and because, due to research we have done recently, we understand the impact of those marital practices on the patterns of genetic variation in this community. We will later study other populations where marriage between relatives or within clans are also common. 

There are two potential clinical benefits of this work. One is that it, if a husband and wife from the same biraderi have had a child with a severe disorder but the genetic cause has not been identified, we should be able to give them more accurate advice about their risks of having another child with the same or another disorder. Secondly, this work may identify genetic changes that cause disorders relatively often in particular communities, which could make it quicker in future to diagnose patients from those communities and improve their clinical care.

Before embarking on this work, we plan to form two different PPI panels with members of communities for whom this is most relevant. The first is likely to be composed of parents of affected children, and the other of other community representatives. The goal is to gauge the views of these community representatives about the utility of this research, including potential sensitivities, and to plan how to communicate it sensitively to the wider community. We are in discussions with the GEL disparities panel about setting these up. Saghira Malik Sharif, a genetic counsellor in Leeds with a lot of experience in this area, is helping with setting up the panels.

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