Familial risk of oral clefts by morphological type and severity: population based cohort study of first degree relativesBMJ 2008; 336 doi: https://doi.org/10.1136/bmj.39458.563611.AE (Published 21 February 2008) Cite this as: BMJ 2008;336:432
- Åse Sivertsen, consultant plastic surgeon12,
- Allen J Wilcox, senior investigator3,
- Rolv Skjærven, professor2,
- Hallvard Andreas Vindenes, consultant plastic surgeon1,
- Frank Åbyholm, professor4,
- Emily Harville, assistant professor5,
- Rolv Terje Lie, professor2
- 1Department of Plastic Surgery, Haukeland University Hospital, No-5021 Bergen, Norway
- 2Department of Public Health and Primary Health Care, University of Bergen, Kalfarveien 1, N-5018 Bergen
- 3Epidemiology branch, National Institute of Environmental Health Sciences, NIH, Durham, NC 27709, USA
- 4Department of Plastic Surgery, Rikshospitalet, N-0027 Oslo, Norway
- 5Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA
- Correspondence to: Å Sivertsen
- Accepted 17 December 2007
Objective To estimate the relative risk of recurrence of oral cleft in first degree relatives in relation to cleft morphology.
Design Population based cohort study.
Setting Data from the medical birth registry of Norway linked with clinical data on virtually all cleft patients treated in Norway over a 35 year period.
Participants 2.1 million children born in Norway between 1967 and 2001, 4138 of whom were treated for an oral cleft.
Main outcome measure Relative risk of recurrence of isolated clefts from parent to child and between full siblings, for anatomic subgroups of clefts.
Results Among first degree relatives, the relative risk of recurrence of cleft was 32 (95% confidence interval 24.6 to 40.3) for any cleft lip and 56 (37.2 to 84.8) for cleft palate only (P difference=0.02). The risk of clefts among children of affected mothers and affected fathers was similar. Risks of recurrence were also similar for parent-offspring and sibling-sibling pairs. The “crossover” risk between any cleft lip and cleft palate only was 3.0 (1.3 to 6.7). The severity of the primary case was unrelated to the risk of recurrence.
Conclusions The stronger family recurrence of cleft palate only suggests a larger genetic component for cleft palate only than for any cleft lip. The weaker risk of crossover between the two types of cleft indicates relatively distinct causes. The similarity of mother-offspring, father-offspring, and sibling-sibling risks is consistent with genetic risk that works chiefly through fetal genes. Anatomical severity does not affect the recurrence risk in first degree relatives, which argues against a multifactorial threshold model of causation.
Contributors: All authors made substantial contributions to the intellectual content of the manuscript and have all approved the final version. ÅS had primary responsibility for writing the paper and analysed the data. AJW originated the study and contributed critical insights in interpretation of data. RS contributed to the design of data files and participated in interpretation of the data. HAV and FÅ provided clinical access to cases and contributed critical insights in interpretation of the data. EH participated in interpretation of the data. RTL originated the study, designed the study, helped in analysis of data, and contributed critical insights in interpretation of data. ÅS is the guarantor.
Funding: This work was supported by grants from the Norwegian Research Council, Helse Vest, and from NIH (2RO1 DE-11948-04). This work was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences and Quality Assurance Foundation II of the Norwegian Medical Association.
Competing interests: None declared.
Ethical approval: Norwegian Data Inspectorate. Studies of anonymous data from health registries do not require review by a regional committee for medical research ethics in Norway.
Provenance and peer review: Not commissioned; externally peer reviewed.