The etiology of PVOD remains unknown. Previous reports have suggested that, although PVOD has no obvious genetic predisposition, it has a significant genetic background [1, 4].
Although the presence of a biallelic EIF2AK4 mutation is sufficient to confirm the diagnosis of PVOD without additional histological confirmation , the precise role of EIF2AK4 mutations in the pathogenesis of PVOD remains unclear. Zeng et al. reported that a novel EIF2AK4 mutation, [c.4833_4836dup (p.Q1613Kfs*10)], predicted an aggressive PVOD phenotype . However, Li et al. described a good response to PAH-targeted drugs in a patient with PVOD carrying the biallelic EIF2AK4 mutation [c.1392delT(p.Arg465fs)] . These controversies suggest that the development of PVOD varies greatly among individuals, and that patients may respond differently to targeted drugs. However, whether this is related to different EIF2AK4 mutation sites in PVOD remains to be further studied.
In our case, the proband was screened for an EIF2AK4 compound heterozygous mutation using WES, which confirmed the final diagnosis of PVOD. Moreover, we detected EIF2AK4 heterozygous mutations in the proband’s parents by fixed-point Sanger sequencing and found a new EIF2AK4 mutation in exon 12 of the patient and his mother. Previous studies have argued that mutations in EIF2AK4 lead to either a defective protein or the absence of protein expression [7, 8]. The general control nonderepressible 2 (GCN2) protein, a serine-threonine kinase encoded by EIF2AK4, has been recently identified as a susceptibility factor driving the etiology of PVOD [2, 7]. Nossent et al. reported that pulmonary artery remodeling and decreased GCN2 expression were the common denominators in all cases of PVOD and revealed a preponderant venous remodeling in young EIF2AK4 mutation carriers as compared with elder non-carriers . In our case, the patient was a young man who responded well to PAH-targeted drugs, unlike in previous studies, which may be related to pulmonary vascular cell proliferation and microvascular remodeling associated with the EIF2AK4 biallelic dysfunction mutation. However, the pathophysiological association between biallelic EIF2AK4 loss-of-function mutations and pulmonary vascular cell proliferation and remodeling remains unclear. To date, no functional studies have assessed the effects of nonsense or frameshift mutations and their truncated protein products on the activity of the encoded EIF2AK4 protein . The absence of a molecular mechanism that relates the abrogated function of the protein to the phenotype remains a major hurdle in our understanding of the disease .
Although the typical pathological changes in PVOD are theoretically easy to understand, lung biopsy specimens of these patients are rare in actual work. Because of the rapidly progressing clinical course and often uncertain diagnosis of PVOD, rapid diagnosis and possible lung transplantation are paramount for survival . Fortunately, with the advancement of technology, WES is widely used to understand the genetic etiology of a disease. An increasing number of PAH centers offer genetic testing and counseling services . Compared to conventional Sanger sequencing, WES is an effective alternative method for genetic diagnosis. The clinical utility of WES will be significantly promoted in the near future with reduction in costs. In the future, we should strengthen the role of NGS in improving the diagnostic efficiency of patients with PVOD with no obvious clinical triad to achieve early detection, diagnosis, and treatment.
Our study has certain limitations. First, we did not have a complete family tree because some family members refused to undergo genetic analysis. In addition, a lung biopsy was not conducted in the proband owing to safety and economic issues. However, current guidelines indicate that heritable PVOD can be diagnosed by identifying pathogenic biallelic EIF2AK4 variants. Last but not the least, the absence of a molecular mechanism that relates the abrogated function of the protein to the phenotype is still a major hurdle in our understanding of the disease.