A cohort study of recurrence patterns among more than 54 000 relatives of oral cleft cases in Denmark: support for the multifactorial threshold model of inheritance
- Dorthe Grosen1,
- Cécile Chevrier2,
- Axel Skytthe1,
- Camilla Bille1,
- Kirsten Mølsted3,
- Åse Sivertsen4,
- Jeffrey C Murray5,
- Kaare Christensen1
- 1Research Centre for the prevention of Infant Mortality and Congenital Illnesses, Institute of Public Health, University of Southern Denmark, Odense, Denmark
- 2Inserm, U625, University of Rennes, Rennes, France
- 3Copenhagen Cleft Palate Centre, Hellerup, Denmark
- 4Department of Plastic Surgery, Haukeland University Hospital, Bergen, Norway
- 5University of Iowa, Department of Paediatrics, Iowa City, USA
- Correspondence to Dr Dorthe Grosen, Research Centre for the prevention of Infant Mortality and Congenital Illnesses, Institute of Public Health, University of Southern Denmark, JB Winsløws Vej 9, DK-5000 Odense, Denmark;
Contributors All authors made substantial contributions to the intellectual content of the manuscript and all have approved the final version. DG and CC had primary responsibility for writing the paper and analysing the data. KC initiated the study, obtained funding and supervised the analyses and the writing of the manuscript. JM helped develop the protocol, provided critical insights into the interpretation of data and helped write the manuscript. CB, KM, and AS assisted with the protocol design, data construction, analysis, and writing of the manuscript. ÅS provided access to Norwegian data and provided critical insights into the interpretation of data. DG is the guarantor.
- Received 12 May 2009
- Revised 20 August 2009
- Accepted 25 August 2009
- Published Online First 14 September 2009
Objectives To determine if the anatomical severity of oral clefting affects familial recurrence in a large population based sample. To provide reliable recurrence risk estimates for oral cleft for first, second, and third degree relatives.
Design Population based cohort study.
Participants 6776 individuals affected with an oral cleft born from 1952 to 2005 and 54 229 relatives.
Main outcome measures Recurrence risk estimates for oral cleft for first, second, and third degree relatives and stratification by severity, specificity, parent of origin effect, and family size for first degree relatives.
Results For cleft lip and palate probands we observed recurrence risks for first, second, and third degree relatives of respectively 3.5% (95% CI 3.1% to 4.0%), 0.8% (95% CI 0.6% to 1.0%), and 0.6% (95% CI 0.4% to 0.8%). Individuals affected by the most severe oral cleft had a significantly higher recurrence risk among both offspring and siblings, eg, the recurrence risk for siblings of a proband with isolated bilateral cleft lip with cleft palate was 4.6% (95% CI 3.2 to 6.1) versus 2.5% (95% CI 1.8 to 3.2) for a proband born with a unilateral defect.
Conclusions Anatomical severity does have an effect on recurrence in first degree relatives and the type of cleft is predictive of the recurrence type. Highly reliable estimates of recurrence have been provided for first cousins in addition to more accurate estimates for first and second degree relatives. These results and the majority of prior data continue to support a multifactorial threshold model of inheritance.
- Recurrence risk
- cleft lip and palate
- multifactorial threshold model
- clinical genetics
- reproductive medicine
- genetic epidemiology
Funding University of Southern Denmark, 5230 Odense M, Denmark and the National Institute of Health, Grant no. R01 DE 11948 - Gene-environment interaction in facial clefts. Other funders: NIH.
Competing interests None.
Ethical approval This study was approved by the Danish Data Protection Agency (case No 92/229MC).
Provenance and peer review Not commissioned; externally peer reviewed.