A new study has identified more common genetic variants associated with increased risk for cleft lip and palate.  Combined with two previous studies (more here and here), there are now four variations that have been associated with this birth defect that affects about one out of every 700 children born.

Clefting results from improper fusing during fetal development of the different elements that will make up the lower part of the face.  For some children only the lip is affected, while others have clefting of both the lip and palate.  Cleft palate alone is much more rare.

An international team led by German researchers analyzed the DNA of 399 people born with cleft lip with or without cleft palate and 1,318 controls.  Many of these people had been included in one of the previous studies that found a genetic association with clefting.  The researchers then examined the most promising variants in 665 families with an affected child.  All of the study subjects had European ancestry.

Two SNPs with significant associations were identified.  The relative risk of cleft lip with or without cleft palate was 1.36 for one copy of the A version of rs7078160, and 2.50 for two copies.  The relative risk was 1.38 for one copy of the G version of rs227731, and 1.91 for two copies. The results were published online yesterday in the journal Nature Genetics.

(23andMe Complete Edition customers can check their data using the Browse Raw Data feature.)

Both rs227731 and rs7078160 are located in regions of the genome previously associated with cleft lip and/or palate in animal models and in humans.

There is some evidence that cleft lip with and without cleft palate are two separate conditions, possibly with different genetic risk factors.  The authors of the current report did not find any difference between the effects of their most significant genetic associations, including rs227731 and rs7078160.  No association of these SNPs was found with cleft palate alone.

The researchers believe that together the previously described variants and these two newly identified SNPs account for a substantial proportion of the risk for sporadic cleft lip with or without cleft palate.  However, they think there are probably still additional genetic variants associated with this condition left to be found.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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Diagnostic imaging of King Tut’s mummy suggests the pharaoh may have had a slightly cleft palate.

Last year researchers reported in Nature Genetics their discovery that a SNP in the gene IRF6, on chromosome 1, is associated with clefting of the lip and/or palate. About one child in 700 is born with clefting, which results from improper fusing during fetal development of the different elements that will make up the lower part of the face. Though some rare conditions are associated with clefting, most cases do not have any identifiable cause.

Now an international team led by German researchers has discovered a second genetic marker that increases the odds of cleft lip and/or palate six-fold among people who inherit the high-risk version of the marker from both parents.

Birnbaum et al. genotyped 224 people who had been born with cleft lips and/or palates and compared them to 383 controls. In the most recent issue of Nature Genetics they report finding an association between clefting and a cluster of SNPs on chromosome 8.

The most statistically significant association was with rs987525. Subjects with one A at the SNP had 2.57 times the odds of clefting compared to those with a C at both copies. And subjects with an A at both copies had about six times the odds of clefting.

(23andMe customers can check their data using SNP rs987525 in the Browse Raw Data feature.)

The stretch of chromosome 8 where rs987525 is located is a particularly featureless region of the human genome, so it is difficult to pin down the mechanism behind the association. But whatever that mechanism is, the authors estimate that it accounts for 41% of the clefting cases in the population they studied.

Clefting is most common among Asian populations, with intermediate incidence among Europeans and the lowest rates observed among Africans. Yet the high-risk version of rs987525 shows the opposite distribution; it is almost three times more common among Africans than Europeans, and nearly absent among Asians.

In their Nature Genetics paper, the authors offer several possible explanations for this anomaly. It could be that there are other genetic or environmental factors associated with clefting that remain undiscovered, or that the linkage between rs987525 and the as-yet-unknown genetic mechanism it is pinpointing differs in the various continental populations.

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John Henry “Doc” Holliday is rumored to have been born with a cleft lip and palate.

Beginning in the fourth week of gestation, the cells of a developing human fetus begin a complex program of rearrangements to form what will eventually become a child’s face.

In about one out of every 700 births this process goes awry. Genetic and environmental factors, acting alone or in concert, prevent the cells of the face from coming together properly, resulting in cleft lip and/or cleft palate. Though clefting can cause problems with feeding, ear infections and tooth development, surgery and other treatments can allow children to grow up to lead perfectly normal lives.

Although there are some rare genetic syndromes that cause cleft lip and/or palate, most cases of clefting are probably due to a combination of genetic factors that increase risk slightly and environmental triggers such as exposure to certain infections, some medications, alcohol and drug use, cigarette smoking, and certain vitamin deficiencies, especially during early pregnancy.

Fedik Rahimov and colleagues have now found the first common genetic variant, or SNP, strongly associated with cleft lip. Their results, published online Sunday in Nature Genetics, show that the common, non-inherited form of this condition is linked to a gene called IRF6 that was previously associated with a rare, dominantly inherited clefting disorder called Van der Woude syndrome.

Using 280 European families affected by cleft lip only, the researchers found that having one A at rs642961 increased the risk of this condition 1.91 times over the risk of those with two Gs at this SNP. That increase in risk rose to 2.29 times for people with two As.

Approximately 50% of people born with cleft lip also have a cleft palate. The link between rs642961 and cleft lip with cleft palate was not significant. Having cleft palate alone (no cleft lip) is rare, and there was no evidence that rs642961 was linked to this condition either.

(23andMe customers can check their data at a proxy SNP, rs861020, The version that increases risk of cleft is A for this SNP as well).

The authors note that the A version of rs642961 is least commonly found in Africans and most common in Native Americans, which mirrors the different levels of cleft lip and palate found in these populations. Because this research was conducted in Europeans, determining whether this SNP is associated with cleft lip in these populations will require further research.

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