Scientists find genetic mutation that causes cleft lip and palate, heart defects

Cleft lip and cleft palate are common birth defects affecting thousands of babies every year in the United States. New research uncovers the genetic mechanism behind these defects.

The Centers for Disease Control and Prevention (CDC) report that approximately 2,650 babies are born with a cleft palate every year, and another 4,440 with a cleft lip.

Cleft lip and palate (CLP) occur when the tissue that forms the lip and the roof of the mouth does not join properly during pregnancy.

Many of the babies affected also have speech impediments and experience difficulties with feeding. Sometimes hearing and vision impairment, or even heart defects, can accompany CLP.

While these orofacial birth defects are common, their cause remains largely unknown. Genetic changes as a result of the mother's diet or medication are thought to play a role, but the exact genetic mechanism is not fully understood.

A team of international researchers from the United Kingdom, Canada, Saudi Arabia, and the U.S. has set out to investigate the genetic mutations behind CLP and their accompanying heart defects.

The research was published in the journal PLOS Genetics.

Searching for the CLP-causing gene mutation

The team, led by Martina Muggenthaler from the University of Exeter in the U.K., examined people with CLP from Amish and Northern Saudi Arabian families.

They identified five Amish children between 4-16 years old with syndromic CLP, and two children aged 7 and 12 years from an Arabic family.

Using genetic mapping, the researchers looked for the chromosomal location of the gene responsible for the disease. They performed a genome-wide single nucleotide polymorphism (SNP) study. SNPs are the most common form of variation in people's DNA, often acting as biological markers that help scientists to locate disease genes.

Next, Muggenthaler and team undertook a whole exome sequence analysis of a single individual with CLP in order to identify the mutation causing the disease.

After adjusting for various factors such as SNP call quality and population frequency, the team found only one pathogenic variant in the HYAL2 gene.

Mutations in the HYAL2 gene responsible for CLP

The HYAL2 gene encodes hyaluronidase 2, an enzyme responsible for degrading hyaluronan (also known as hyaluronic acid).

Hyaluronan is a carbohydrate polymer usually found in connective tissue and the hard palate.

Researchers performed enzyme assays, which revealed that the mutations reduced the levels of the HYAL2 protein. This, in turn, inhibited the metabolism of hyaluronic acid.

Given that hyaluronan is found in the connective tissue of many parts in the body, including the heart, the researchers hypothesized that mutations in the HYAL2 gene would cause CLP and heart defects in mice.

They therefore performed further tests - including histological studies - on mice that lacked the HYAL2 protein. These studies revealed underdevelopment in the mice bones, as well as failed fusion of the palate tissue.

Further studies found cor triatriatum sinister - a common heart defect that accompanies CLP, in which the heart grows a third atrial chamber - in 50 percent of the mice lacking HYAL2.

The research by Muggenthaler and team shows the importance of hyaluronan in the development of the palate and heart.

"This finding is important as it highlights a new molecular cause for orofacial clefting which is likely to be relevant to other as yet unidentified genetic causes of the condition," says co-author Prof. Andrew Crosby, from the University of Exeter.

Study co-author Dr. Emma Baple, also from the University of Exeter, adds: "It also provides the first molecular cause of the heart defect cor triatriatrum sinister."

Learn why a daily supplement of folic acid is recommended to prevent birth defects.