Rare Inherited Mutations Shown to Cause Severe Childhood PAH

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by Steve Bryson, PhD |

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Rare mutations in the ATP13A3 gene caused a severe inherited form of childhood-onset pulmonary arterial hypertension (PAH), a case study of three families showed.

These findings demonstrate the “growing importance” of genetic testing in patients with childhood-onset PAH, the scientists said, noting that the genetic basis of the disease is “heterogeneous, with at least 26 genes displaying putative evidence for disease causality.”

The researchers noted that PAH has many potential causes, with approximately 15 to 20% of patients having familial, or heritable PAH, caused by genetic mutations passed down from parents to their biological children. In cases with no identifiable cause, the disease is referred to as idiopathic PAH or IPAH.

“Approximately 80% of IPAH cases remain genetically undiagnosed,” the scientists wrote, highlighting the need for genetic tests.

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The study, “Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality,” was published in the Journal of Medical Genetics.

PAH is characterized by abnormally high blood pressure in the arteries that transport blood from the heart to the lungs, which causes the right ventricle of the heart to work harder to pump blood.

Among the genetic mutations that are passed down to children are ones occurring in the BMPR2 gene, and more recently identified, the ATP13A3 gene, which has been associated with adult-onset PAH.

Compared with adult-onset PAH, childhood-onset PAH — called cPAH — is marked by more severe disease, resistance to therapies, and poor survival. However, the contribution of ATP13A3 mutations to childhood-onset PAH is unknown.

Now, researchers in the U.S., the U.K., and Slovenia report on three families with a new form of cPAH that affected five children under the age of 3. This new cPAH form is due to mutations (variants) in both ATP13A3 gene copies (biallelic) — one each inherited from the mother and the father.

In the first family, one of Slovenian descent, the child showed right heart failure at the age of 2.5 years. An echocardiogram showed right ventricular and right atrial enlargement; as such, he was diagnosed with PAH. Although he was treated with medications for high blood pressure, the boy died at age 4 due to right heart failure.

His brother was monitored from birth, but at 2.5 years of age, echocardiography revealed high pressure in the right ventricle with heart enlargement. Further tests showed elevated pulmonary arterial pressure. The child underwent a lung transplant at 4.5 years of age, but despite his extended treatment, died at 8.5 years after contracting pneumonia. Both parents and a sister remain healthy with no evidence of PAH.

In both affected children, genetic analysis showed a c.2563 G to A mutation in both ATP13A3 gene copies, in which G stands for guanine and A for adenine, both building blocks of DNA. The grandparents of the affected brothers lived in nearby villages, potentially indicating a common ancestor. This same mutation was recently reported in people in southern Europe.

In the second family, who had Ashkenazi Jewish ancestry, a boy age 6 months was investigated due to delayed development and episodes of cyanosis, or bluish-purple skin. Echocardiography showed severe PAH with high right ventricle blood pressure. Increased pressure in the pulmonary arteries also was demonstrated.

Following a cardiac arrest during recovery from testing, he was given oxygen support for 10 days. Despite further maintenance therapy, he remained in critical condition and died of sepsis (a life-threatening response to an infection) and PAH at age 11 months.

At 1 week of age, his sister developed persistent cyanosis, with low oxygen and respiratory distress. High right ventricle pressure was seen on an echocardiogram. She was initially treated with therapies that dilated blood vessels and put on mechanical ventilation. After responding to treatment, she was discharged at 2 months of age.

At 9 months, she developed high arterial blood pressure, which did not improve with additional treatment, including 100% oxygen. She died at 17 months following a lung infection. Both parents and two siblings were unaffected with no signs of PAH.

Both affected children carried double ATP13A3 mutations in both gene copies. One was identified as c.2227 C to T, in which C stands for cytosine and T for thymine, the other two building blocks of DNA. The other mutation was a duplicate T in the DNA sequence (c.2549dupT). Both parents and two siblings had one mutation in one of the two gene copies.

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From the third family, of Anglo-European ancestry, a 22-month-old girl was treated for severe PAH and right heart failure. Echocardiography and chest CT scans demonstrated right ventricle dilatation and right atrial enlargement. She also had high blood pressure in the pulmonary arteries.

Given her severe condition, she underwent balloon dilation of the foramen ovale — a small hole in the wall between the two upper chambers of the heart — and was given various medications for one year. Her blood flow only moderately improved, and she had a mild response to oxygen as well as inhaled nitric oxide, used to dilate blood vessels. Despite this treatment, she showed signs of right heart failure six months later.

As a result, she underwent a Potts shunt — a surgical procedure that creates a connection between the descending aorta, the large artery that carries blood to the body, and the left pulmonary artery. This is done to optimize pulmonary blood flow and decompress the right ventricle. After three months, her exercise tolerance markedly improved. Both parents and two siblings remained without PAH symptoms.

Genetic screening identified different mutations in both ATP13A3 gene copies: c.3079dupT and a c.3685 G to T. Both parents and one unaffected sibling carried one of the two mutations.

“We report biallelic variants in ATP13A3 associated with very early age of PAH onset and high mortality in three independent families. The five variants are extremely rare or absent from gnomAD [Genome Aggregation Database] and predicted to be deleterious missense [damaging and causing a change in the amino acid sequence of the protein] or loss-of-function variants,” the scientists wrote.

“These findings demonstrate the growing importance of comprehensive genetic analyses in … cPAH populations,” they concluded.