Pulmonary arterial hypertension

Gene: EIF2AK4

Comment on mode of inheritance: Leaving the mode of inheritance as BOTH mono and biallelic although OMIM just has autosomal recessive because there is a report of a heterozygous variant in this gene in a patient with pulmonary veno-occlusive disease.

Created: 14 Apr 2022, 6:46 p.m. | Last Modified: 14 Apr 2022, 6:46 p.m.

Panel Version: 2.21

Mode of inheritance - in OMIM this gene is associated with Pulmonary venoocclusive disease 2, OMIM:234810 with an autosomal recessive mode of inheritance.

Most reported cases of patients with Pulmonary capillary hemangiomatosis (PCH)/Pulmonary veno-occlusive disease are have biallelic variants (homozygous or compound het) e.g.
PMID: 24292273 - Eyiers et al 2014 - 18 cases (13 familial, 5 sporadic)
PMID: 24135949 - Best et al 2014 - 3 cases (1 familial, 2 sporadic)

However, there are 2 reports of heterozygous variants in EIF2AK4 in patients with a relevant phenotype, 1 in combination with a variant in another disease associated gene.

PMID: 27809840 - Eichstaedt et al 2016 - a family of 10 with 3 members with inherited pulmonary arterial hypertension (HPAH). Those with HPAH were found to have two pathogenic heterozygous mutations: a frame shift mutation in BMPR2 and a splice site mutation in the EIF2AK4. BMPR2 is associated with the autosomal dominantly inherited conditions Pulmonary hypertension, familial primary, 1, with or without HHT (OMIM:178600) and Pulmonary venoocclusive disease 1 (OMIM:265450). Only those family members with a both variants developed manifest HPAH; 2 family members who carried the BMPR2 mutation only did not develop manifest HPAH. Not all family members were sequenced so it is possible that members with just the EIF2AK4 were asymptomatic.

PMID: 32631303 - Zheng et al 2020 - 14-year-old female patient initially clinically suspected for PAH, who had Pulmonary veno-occlusive disease triad features. WES identified a novel heterozygous EIF2AK4 mutation at c.4833_4836dup (p.Q1613Kfs*10).

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Created: 14 Apr 2022, 6:42 p.m. | Last Modified: 14 Apr 2022, 6:42 p.m.

Panel Version: 2.18

Publications

• 24292273
• 24135949
• 27809840
• 32631303

Green List (high evidence)

Initial gene list and info collated by Ian Berry Leeds Genetics Laboratory November 2018 on behalf of the GMS Respiratory specialist test group. Gene Symbol submitted: EIF2AK4; Suggested initial gene rating: Green; Evidence for inclusion: OMIM Pulmonary venoocclusive disease 2; causes PAH.; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given

Created: 6 Dec 2018, 2:01 p.m.

Comment on publications: added new publication on the Phenotypic Characterisation of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically with Pulmonary Arterial Hypertension.

Created: 11 Oct 2017, 8:42 a.m.

Comment on phenotypes: added IPAH phenotype due to pmid:28972005

Created: 11 Oct 2017, 8:41 a.m.

From Hadinnapola et.al 2017 (PMID: 28972005): Eight hundred and sixty-four patients with idiopathic or heritable PAH and 16 with PVOD/PCH were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of PVOD/PCH. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (KCO: 33 [IQR: 30 - 35] % predicted) and younger age at diagnosis (29 [23 - 38] years) as well as more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest, compared to PAH patients without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. PAH patients with biallelic EIF2AK4 mutations had a shorter survival. Conclusions -Biallelic EIF2AK4 mutations are found in patients classified clinically as idiopathic and heritable PAH. These patients cannot be identified reliably by CT, but a low KCO and a young age of diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

Created: 11 Oct 2017, 8:36 a.m.

In the biallelic state (compound heterozygotes or variant homozygotes) mutations is EIF2AK4 have been associated with PVOD/PCH. EIF2AK4 has been identified in 6 families with autosomal recessive PAH from the same itinerant Iberian community (PMID: 25917481,25512148) suggesting a founder EIF2AK4 mutation. However in PMID 27809840 (2016) EIF2AK4 mutations were also found in another large single family but with autosomal dominantly inherited pulmonary arterial hypertension (HPAH) and incomplete penetrance of bone morphogenic protein receptor 2 (BMPR2) mutations which suggested that EIF2AK4 can also contribute to autosomal dominantly inherited HPAH, since other reported instances identified a recessive form of HPAH. Only those family members with a co-occurrence of two mutations developed manifest HPAH. Two homozygous missense mutations have been reported in PMID: 27884767 (2017), this was the first report of biallelic pathogenic EIF2AK4 mutations found in patients diagnosed clinically with HPAH and it is thought that the Identification of pathogenic biallelic EIF2AK4 mutations can aid clinicians in differentiating HPAH from heritable PVOD or PCH. PMID:28087362 provides a definitive description of PVOD/PCH and the effect of EIF2AK4 mutations.

Created: 22 Jun 2017, 2:35 p.m.

This is a ultra-rare form of PAH, pulmonary veno-occlusive disease (PVOD) or pulmonary capillary haemangiomatosis, has been shown (especially in families with PVOD) to be largely due to recessive biallelic mutations in the gene EIF2AK4, which encodes a kinase for the integrated stress response. As with other recessive rare conditions, consanguinity is more common in the parents who are carriers for the EIF2AK4 mutation PMID: 27694411

Created: 21 Jun 2017, 12:14 p.m.

Changed to Green status- reference NIHR-RD BRIDGE project. In a cohort of 890 PAH cases, there were 7 cases with homozygous EIF2AK4 variants and 6 cases with potential compound heterozygous EIF2AK4 variants. It was also noted that EIF2AK4 mutation carrier present at younger age.

Created: 19 Jun 2017, 12:06 p.m.

Comment on publications: added recent publication (2017) PMID: 27884767

Created: 19 Jun 2017, 11:53 a.m.

Comment on list classification: Changed to Green status- reference NIHR-RD BRIDGE project

Created: 19 Jun 2017, 10:11 a.m.

Comment on mode of inheritance: changed MOI due to paper PMID:27809840 with AD

Created: 14 Jun 2017, 12:04 p.m.

Publications

• 28972005

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Pulmonary veno-occlusive disease; PVOD; Pulmonary capillary haemangiomatosis; PCH

Publications

• 24292273