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Net als vorig jaar zijn we druk bezig geweest met de actieve werving en includering van deelnemers voor dit onderzoeksproject. Het vinden van geschikte consanguïne paren voor het case-control onderzoek heeft hierbij onze hoogste prioriteit. De strikte inclusiecriteria, evenals de niet altijd makkelijk te benaderen doelgroep, maakt dat het includeren van verwante paren nog altijd een grote tijdsinvestering vergt.

In Nederland hebben we goede contacten in ziekenhuizen die ons helpen met het verzamelen van geschikte deelnemers aan het onderzoek, en daarnaast hebben we onze buitenlandse contacten uitgebreid. We verwachten dat we door deze gezamenlijke inspanning medio van dit jaar voldoende paren geïncludeerd zullen hebben om aan de laboratorium werkzaamheden en de analyses te beginnen.

Via diverse klinisch genetische centra en verloskundigenpraktijken zijn we ook doorgegaan met het vinden van paren met een kinderwens of eerste zwangerschap. Op deze wijze hebben we voor ons cohort diverse paren kunnen includeren.

We hebben in de zomer van 2010 een artikel gepubliceerd in het tijdschrift BMC Medical Genetics, waarin we de methode van ons onderzoek beschrijven (zie het tabblad Resultaten).

 

Resultaten
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In augustus 2010 werd het volgende artikel gepubliceerd:

Teeuw, M. E., Henneman, L., Bochdanovits, Z., Heutink, P., Kuik, D. J., Cornel, M. C. et al. (2010). Do consanguineous parents of a child affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related parents with healthy offspring? Design of a case-control study. BMC.Med.Genet., 11, 113.

Samenvatting van de aanvraag

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Children of consanguineous couples , i.e. couples in which both partners have a common ancestor, are at increased risk of morbidity and early mortality. The level of risk depends on the degree of relationship of their parents. For instance for children of first cousins the risk of congenital/genetic disorders and of early mortality is 2-3% and about 4%, respecively, above the level for children of unrelated partners. The excess risk is mainly caused by autosomal recessive disorders, most of which have not manifested themselves in the wider family yet.

 

It is estimated that one in every 12 children world-wide has consanguineous parents. The prevalence of consanguinity is 20 or more percent in one-sixth of the world population. In the Netherlands consanguinity is found especially in migrant populations e.g. in Turkish and Moroccan immigrants and their descendants. It is understood that 25-30% of the marriages in these communities are first cousin matings.

 

If one compares the 2-4% excess risk in offspring of first cousins with the 25% risk for children of parents who are carriers for an autosomal recessive disease, one has to conclude that of all first cousin couples a minority is at significant high risk (25% or more), while the majority has no or a very limited excess risk. The ambition of this research is to develop and test a method which can identify among all consanguineous couples the ones which are at high risk.

 

The excess risk of autosomal recessive disease in the offspring of consanguineous couples is conditional on: 1) the presence of identical alleles in both parents, descending from the common ancestor(s); 2) the presence of pathological mutations in the ancestral alleles. The more DNA identical by descent is shared by parents, the higher the risk of excess morbidity and mortality in their children. The proportion of shared DNA can be assessed by genome-wide single nucleotide polymorphism (SNP) analysis.

 

In this research we want to answer the following questions:

 

1. Do consanguineous parents with children affected by autosomal recessive diseases share more DNA indeed than consanguineous parents who are believed to be related to the same degree, but only have healthy children? This question will be approached by means of a case-control design, involving 100 cases and 100 controls. We will combine data on cases and controls from an ongoing research project in Oman with data from Dutch cases and controls.

 

2. What exact risk figures should be given for the proportions of shared DNA in different couples? Here we will employ a cohort design. Two cohorts will be constituted, a historic cohort and a current cohort. First estimates will be obtained from the historic cohort. The current cohort will enable us to arrive at more precise figures in the future.

 

3. Do consanguineous couples believe that SNP analysis or a further improvement towards exact identification of the diseases for which their children are at risk, would be of help to them, influence reproductive decision making, and if so to what extent? This question will be approached by means of structured interviews in 60-100 partners from the current cohort.

 

Implementation of the proposed method is conditional on the results of this research and not a part of this project. Participants will not be informed about their own results before we can be confident of the precise risk figures.

 

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