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.
OBJECTIVE
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.


METHODS
Population based cohort study.


METHODS
Denmark.


METHODS
6776 individuals affected with an oral cleft born from 1952 to 2005 and 54 229 relatives.


METHODS
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.
Grosen
Dorthe
D
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. dgrosen@health.sdu.dk
Chevrier
Cécile
C
Skytthe
Axel
A
Bille
Camilla
C
Mølsted
Kirsten
K
Sivertsen
Ase
A
Murray
Jeffrey C
JC
Christensen
Kaare
K
D002971:Cleft Lip / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics; D002972:Cleft Palate / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics; D015331:Cohort Studies; D003718:Denmark / Q000453:epidemiology; D004200:Diseases in Twins / Q000453:epidemiology / Q000235:genetics; D005190:Family; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D020412:Multifactorial Inheritance; D012008:Recurrence; D012042:Registries; D013997:Time Factors; D014427:Twins