EIF2AK4 mutation as “second hit” in hereditary pulmonary arterial hypertension

Abstract

BackgroundMutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene have recently been identified in recessively inherited veno-occlusive disease. In this study we assessed if EIF2AK4 mutations occur also in a family with autosomal dominantly inherited pulmonary arterial hypertension (HPAH) and incomplete penetrance of bone morphogenic protein receptor 2 (BMPR2) mutations.MethodsClinical examinations in a family with 10 members included physical examination, electrocardiogram, (stress)-echocardiography and lung function. Manifest PAH was confirmed by right heart catheterisation in three affected subjects. Genetic analysis was performed using a new PAH-specific gene panel analysis with next generation sequencing of all known PAH and further candidate genes. Identified variants were confirmed by Sanger sequencing.ResultsAll living family members with manifest HPAH carried two pathogenic heterozygous mutations: a frame shift mutation in the BMPR2 gene and a novel splice site mutation in the EIF2AK4 gene. Two family members who carried the BMPR2 mutation only did not develop manifest HPAH.ConclusionsThis is the first study suggesting that EIF2AK4 can also contribute to autosomal dominantly inherited HPAH. Up to now it has only been identified in a recessive form of HPAH. Only those family members with a co-occurrence of two mutations developed manifest HPAH. Thus, the EIF2AK4 and BMRPR2 mutations support the “second hit” hypothesis explaining the variable penetrance of HPAH in this family. Hence, the assessment of all known PAH genes in families with a known mutation might assist in predictions about the clinical manifestation in so far non-affected mutation carriers.

Clinical and genetic characteristics of pulmonary arterial hypertension in Lebanon

“…The fact that in both cases we do not have a clear answer about the pathogenicity of the mutation prompted us to look at other “modifiers” in the pathway leading to PAH involving BMPR2 . Compound mutations within the BMPR2 pathway have been hypothesized and recently predicted in the pathogenesis of the disease [ 32 ]. This is highlighted more in mutations that are otherwise identified as benign mutations, rendering the analysis of genetic variants trickier.…”

Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension

“…Such locus heterogeneity in HPAH has already been reported by many different studies. These include the alteration of BMPR2 15 16 and CBLN2 17 gene expression, second-hit mechanisms of BMPR2 with its promoter19 or with EIF2AK4 mutations,18 as well as somatic chromosome abnormalities in the affected lungs 20. These multiple findings support an oligogenic architecture of HPAH.…”

The role of genomics and genetics in pulmonary arterial hypertension

“…Conversely, in the composite class model, a variant in one gene is sufficient to produce the phenotype, but an additional variant in a second gene impacts the disease phenotype or alters the age of onset 122 . The latter model seems to be plausible in PAH, where co-occurrence of the variants in different PAH risk genes has been reported to impact on disease onset and penetrance 123 . Patients harbouring deleterious variants in more than one PAH risk gene were reported in small 124 and large cohorts of HPAH patients 8 .…”