SOX17 Gene May Contribute to PAH with Congenital Heart Disease, Study Suggests

SOX17 may be a risk gene that contributes to pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD), as well as to idiopathic and/or familial PAH, according to researchers.

Their study, “Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease,” was published in the journal Genome Medicine.

Current evidence indicates that CHD occurs in up to 30% of adult-onset and 75% of pediatric-onset cases of PAH. The surgical repair of heart defects may not eliminate PAH, which may also recur years after surgery.

Although investigators believe that genetic factors are important in PAH-CHD, no major risk gene has been discovered for the disease.

A total of 11 risk genes have been identified in PAH alone, several of which are involved in a molecular pathway important in blood vessel formation and embryonic heart development. One example is mutations in the BMPR2 gene, which, although common in PAH, has a much lower frequency in PAH-CHD.

Underlying the complexity of CHD genetics, no single risk gene is associated with more than 1% of cases. However, rare, inherited variants in genes coding for heart structural proteins, as well as regulators of gene expression or DNA packaging in the cell nucleus, account for approximately 10% of CHD cases.

Researchers from Columbia University Medical Center in New York, aiming to identify new genetic causes of PAH-CHD, conducted a type of molecular analysis called exome sequencing — which determines the sequence of the gene portions, called exons, that contain the information to make proteins — in 256 PAH-CHD patients.

The team first assessed rare gene variants classified as deleterious, meaning they affect protein function and increase an individual’s risk of developing a disorder. Data from PAH-CHD patients were then compared to a separate group of 413 idiopathic and familial PAH patients without CHD.

The results identified SOX17 as a new risk gene candidate, implicated in up to 3.2% of PAH-CHD cases.

SOX17 provides instructions to make a protein involved in embryonic development, determination of cell fate, and in the formation of blood vessels. Three of the SOX17 rare deleterious mutations were located in a region responsible for DNA binding.

Also, a high concentration of rare deleterious variants was found in 149 possible targets of the SOX17 protein, many of which being highly produced in developing blood vessels of the heart and lungs.

Of the total 13 patients (mean age 14.2) with SOX17 variants, nine had pediatric-onset disease. Most patients had severe PAH, including right ventricular hypertrophy (enlargement) and requiring chronic intravenous vasodilator — blood vessel widening — treatment.

In patients with PAH but without CHD, rare deleterious variants of SOX17 occurred in 0.7% of cases.

“These data strongly implicate SOX17 as a new risk gene contributing to PAH-CHD as well as idiopathic/familial PAH,” the researchers wrote, adding that the data also “suggest that rare variants in genes regulated by SOX17 also contribute to PAH-CHD.”

The researchers noted that additional studies expanding the number of PAH-CHD patients analyzing their clinical features will help confirm the role of SOX17 in these patients and the genes it regulates.