Comprehensive genetic study provides new insight into cleft lip and palate

Cleft lip and palate is one of the most common birth defects. Its causes are mainly genetic. However, it is still not clear exactly which genes are affected. A new international study by the University of Bonn now provides new insights. The results are published in the journal Advances in human genetics and genomics, but are already available online.

Researchers at the Institute of Human Genetics at the University Hospital Bonn have combined various data sources in their work. During their research, they discovered five new regions of the human genome in which variations in DNA sequence are associated with an increased risk of malformation. In total, 45 of these risk regions are now known. For some of them, the researchers were also able to show which genes are affected by these changes. “Our results provide new information on the development of the disease, but also on the development of the face in the early embryo as a whole”, explains Dr Kerstin Ludwig.

Ludwig heads a junior Emmy Noether research group at the Institute of Human Genetics at University Hospital Bonn, which focuses on the genetic causes of cleft lip and palate. The average contribution of genes to this frequent malformation is estimated at over 90%. “The genetic contribution is complex,” says Ludwig. “This means that there is not just one gene, but a whole set of genes that contribute to the malformation.”

Data from previously published genomic studies combined

Every human being’s blueprint is stored in their DNA, a sort of giant lexicon of about three billion letters. People are different and the content of their DNA lexicon differs accordingly. However, for people with cleft lip and palate, at least the passages that have something to do with the disease should be similar. Science uses this basic hypothesis: By comparing the DNA of several thousand affected individuals at several million sites, researchers can identify the genetic regions that lead to a higher risk of disease.

A whole series of such “genome-wide association studies” (GWAS) have been published in recent years. “We have now combined the previously published data from GWAS,” says Dr Julia Welzenbach, a postdoctoral fellow in Ludwig’s group who led the just published study. This makes it possible to find even DNA changes that only slightly increase the risk of malformation and are therefore overlooked in individual studies. “In this way, we identified five risk regions that were previously unknown,” explains Welzenbach.

However, this does not automatically contribute to a better understanding of the disease: only about two percent of DNA actually contains genetic information in the sense of direct instructions for building proteins. Science is just beginning to understand what the remaining 98% is for. “The 45 risk regions we know today are all in this 98 percent, which we also call non-coding regions,” Welzenbach explains.

It is now known that part of the non-coding DNA serves to regulate the activity of genes. Some of these DNA regions ensure, for example, that a certain gene is read more frequently or in certain tissues. Such regulatory regions are therefore also called enhancers. Others, however, act like silencers – they turn off certain genes.

Mutations affect regulatory elements of DNA

In each cell, only certain genes are active at any given point in development. In other words, there is a pattern of gene activity specific to cell type and time, and silencers and activators are partly to blame. “Certain regulatory DNA sequences are now known to act as silencers or activators early in the facial development of the embryo,” explains Ludwig. “We were able to show for some of the genetic changes from the GWAS data that they affect these regulatory sequences, and therefore also show which genes increase or decrease their activity as a result.”

Presumably, each of the 45 risk regions known today modifies the effect of an amplifier or silencer. In this way, they disrupt the finely balanced activity pattern of genes that play a role in facial development without error. And it is this disruption, combined with additional factors, that increases an individual’s risk of having a cleft lip and palate.

Participating institutions and funding:

In addition to Bonn University Hospital, the study involved the universities of Manchester, Cologne, Pittsburgh, Connecticut as well as Johns Hopkins University in Baltimore, Emory University in Atlanta and the University of Cantabria. It was funded by the German Research Foundation (DFG, LU 1944-3 / 1).


Journal reference:

Welzenbach, J., et al. (2021) Integrative approaches generate information on the architecture of the non-syndromic cleft lip with or without cleft palate. Advances in human genetics and genomics.

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