BMJ 2008;336:399 (23 February), doi:10.1136/bmj.39470.657685.80 (published 4 February 2008)
Risk of recurrence is higher with cleft palate only
Oral clefts, including cleft lip with or without cleft palate and cleft palate only, have a high rate of familial recurrence compared with many birth defects.1 The cleft can occur in association with other congenital abnormalities, sometimes as part of an underlying recognisable syndrome, or more often as an isolated defect. Inheritance is complex and related to environmental and genetic factors.2 Although a genetic component exists, the precise genetic basis is unclear.
The risks of having a child with an oral cleft that are used when counselling families at increased risk are based on empirical figures derived from studies that have several limitations, such as inclusion of syndromic cases, the grouping of all oral clefts together, incomplete ascertainment, and a lack of longitudinal data.
In their accompanying paper, Sivertson and colleagues report a longitudinal population based study of the risk of non-syndromic oral clefts in Norwegian families.3 They analyse the type and the severity of the cleft in the index case. Norway has an excellent model for generating useful epidemiological data for oral clefting because of the high case ascertainment within a defined population and accurate documentation of clinical cases.
The study finds that the relative risk of cleft recurrence in first degree relatives is 32 (95% confidence interval 24.6 to 40.3) for any cleft lip and 56 (37.2 to 84.8) for cleft palate alone. This suggests that genetics contributes more to cleft palate alone than to cleft lip. The risk of clefts in children of affected mothers was similar to the risk of clefts in children of affected fathers, and the parent-offspring risk was similar to the sibling-sibling risk. The severity of the cleft in the presenting patient and the patient?s sex did not affect the risk of having a cleft. There was also a threefold greater risk of cleft lip after a case of cleft palate alone, and vice versa (crossover risk).
The finding of a higher risk if the first degree relative has cleft palate alone compared with cleft lip differs from the risk figures commonly used in the United Kingdom,4 5 where relatives of a person with non-syndromic cleft lip are thought to have had a higher familial risk than relatives of someone with non-syndromic cleft palate only. Previous studies have often excluded data on cleft palate alone, as this defect may be missed at birth, which makes accurate analysis difficult.6
Siverston and colleagues? data may alter the empirical risks given by geneticists and genetic counsellors to first degree relatives of people with cleft palate alone. A tabulated form giving the results as a percentage risk would be useful for clinicians involved in the care of patients with oral clefts. Parents can relate more to a percentage risk of a cleft in a further pregnancy, rather than being told that the risk is 56 times higher than in the general population. While these figures may apply to northern European populations, the heritability of oral clefts may vary in different ethnic groups. Other counselling questions could also be answered by the dataset, such as how does the risk vary for second and third degree relatives? And what is the risk for half siblings?
Recent evidence suggests that folic acid supplements may reduce cases of cleft lip with or without cleft palate by about a third, but not cases of cleft palate alone.7 This is consistent with the greater familial risk reported for cleft palate alone, as genetic factors may be less susceptible to such environmental influences.
Cleft lip with or without cleft palate and cleft palate alone are thought to be genetically distinct. The specificity of the cleft type in Sivertson and colleagues study reinforces this notion, with a low crossover risk of three between cleft lip and cleft palate alone in families. This crossover risk may partly be accounted for by the contribution of dominantly acting genes, including MSX1 and IRF6, which may play a part in all forms of oral cleft.8 9 It would be interesting to analyse these genes in families where one member has a cleft lip with or without cleft palate and another has cleft palate only.
The reported absence of an effect of cleft severity on the risk of familial recurrence has implications for genetic counselling. Parents whose child has a mild form of cleft, such as a unilateral cleft lip, have the same risk of subsequently having a child with a severe cleft as those whose child has a severe cleft. In addition, a severe cleft in one child does not increase the risk of having another severely affected child.
The study raises questions about our understanding of the mechanisms of clefting. A multifactorial threshold model for oral clefts would predict that the greatest familial risks would be for relatives of the most severely affected cases in the least frequently affected sex (a bilateral cleft lip and palate in a female), but this was not shown. Differences between single gene disorders and complex inheritance are becoming less well defined, and the genetics of clefting is not easily explained by a single genetic model.
The genetic basis of non-syndromic clefting is complex and not well understood. Gene-gene and gene-environment interactions probably play important roles. Well designed epidemiological studies will help molecular research to tease out the contributing factors of this common birth defect and may lead to the identification of preventative factors in the future.
Melissa Lees, consultant in clinical genetics
1 North East Thames Regional Genetics Service and North Thames Cleft Service, Great Ormond Street NHS Trust, London WC1N 1EH
Provenance and peer review: Commissioned; not externally peer reviewed.