Written by Charlotte Harrison, Science Writer
A study published in eLife has identified new genes involved in a rare life-threatening heart disease that occurs in infants, called hypoplastic left heart syndrome (HLHS). This new understanding of the underlying pathobiology of HLHS means we are another step closer to finding better ways to treat HLHS patients.
HLHS is a severe congenital heart disease in which the left ventricle is underdeveloped and cannot pump oxygenated blood. There are likely many genes involved in HLHS.
To look for genes that contribute to HLHS, the authors first analysed whole genome sequencing data from a prioritized family, in which the parents of the infant with HLHS were genetically related. This genetic data focused the gene search on key genes, as the infant was postulated to have a rare homozygous form of HLHS.
This analysis prioritised nine candidate genes, which were then tested for function in drosophila heart models. Heart-specific knockdown of one of the tested genes, the mitochondrial MICOS complex subunit Chchd3/6, dramatically compromised heart contractility, reduced levels of actin and myosin, decreased ATP levels and induced mitochondrial defects.
Further analysis of genome data from 183 HLHS patients and their parents showed genetic variants in Chchd3/6 were present in other individuals with HLHS.
The authors postulate that the Chchd3/6-driven phenotype could contribute to early HLHS manifestations or heart failure complications later in life.
Because HLHS involves many genes, the authors next tested 60 more candidate genes to see if they interacted with Chchd3/6 in fly hearts. Here, knockdown of Cdk12 (an activator of RNA polymerase II), RNF149 (an E3 ubiquitin ligase) or SPTBN1 (a scaffolding protein) had synergistic effects on heart dysfunction when tested in combination with Chchd3/6 knockdown.
The authors note that the finding suggests that diverse pathways are involved in HLHS.
With regards to how the candidate genes cause heart defects, “one hypothesis is that because certain gene variants make it harder for the heart to contract, blood can’t flow as easily to the left side of the heart, thus compromising its proper formation,” said the authors in a press release. “This could lead to the types of abnormalities seen in HLHS.”
The authors stress that HLHS is a complicated, multigenetic disorder that is far from being treatable with options other than multiple surgeries. “[Yet one day] it may be possible that increasing the activity of one of these genes could be enough to strengthen the heart and reduce the risk of heart complications,” they concluded.