Pulmonary arterial hypertension

Gene: EIF2AK4

Green List (high evidence)

EIF2AK4 (eukaryotic translation initiation factor 2 alpha kinase 4)
EnsemblGeneIds (GRCh38): ENSG00000128829
EnsemblGeneIds (GRCh37): ENSG00000128829
OMIM: 609280, Gene2Phenotype
EIF2AK4 is in 1 panel

2 reviews

Louise Daugherty (Genomics England Curator)

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

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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

Publications

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • NHS GMS
  • Expert list
  • Expert Review Green
  • Literature
Phenotypes
  • Pulmonary venoocclusive disease 2, 234810
  • PVOD
  • pulmonary capillary hemangiomatosis
  • PCH
  • Heritable pulmonary arterial hypertension
  • HPAH
  • Pulmonary arterial hypertension
  • Idiopathic pulmonary arterial hypertension
  • IPAH
OMIM
609280
Clinvar variants
Variants in EIF2AK4
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

6 Dec 2018, Gel status: 3

Added New Source, Status Update

Louise Daugherty (Genomics England Curator)

Source NHS GMS was added to EIF2AK4. Rating Changed from Green List (high evidence) to Green List (high evidence)

4 Jun 2018, Gel status: 3

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: EIF2AK4 were set to 25512148; 25917481; 24135949; 24292273; 27809840; 26320113; 26387786; 27884767; 27694411; 28087361; 28087362; 28972005; 29844075

11 Oct 2017, Gel status: 4

Set publications

Louise Daugherty (Genomics England Curator)

Publications for EIF2AK4 were set to 25512148; 25917481; 24135949; 24292273; 27809840; 26320113; 26387786; 27884767; 27694411; 28087361; 28087362;28972005

11 Oct 2017, Gel status: 4

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for EIF2AK4 were set to Pulmonary venoocclusive disease 2, 234810; PVOD; pulmonary capillary hemangiomatosis; PCH; Heritable pulmonary arterial hypertension; HPAH; Pulmonary arterial hypertension; Idiopathic pulmonary arterial hypertension;IPAH

22 Jun 2017, Gel status: 4

Set publications

Louise Daugherty (Genomics England Curator)

Publications for EIF2AK4 were set to 25512148; 25917481; 24135949; 24292273; 27809840; 26320113; 26387786; 27884767; 27694411;28087361;28087362

22 Jun 2017, Gel status: 4

panel promoted to version 1

Louise Daugherty (Genomics England Curator)

Panel reviews were assessed, and panel was revised according to reviews and further in-house curation.

22 Jun 2017, Gel status: 4

Upload gene information

Louise Daugherty (Genomics England Curator)

EIF2AK4 was added to Pulmonary arterial hypertensionpanel. Sources: Expert list

21 Jun 2017, Gel status: 4

Set publications

Louise Daugherty (Genomics England Curator)

Publications for EIF2AK4 were set to 25512148; 25917481; 24135949; 24292273; 27809840; 26320113; 26387786; 27884767;27694411

19 Jun 2017, Gel status: 4

Set publications

Louise Daugherty (Genomics England Curator)

Publications for EIF2AK4 were set to 25512148; 25917481; 24135949; 24292273; 27809840; 26320113; 26387786; 27884767

19 Jun 2017, Gel status: 4

Gene classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

14 Jun 2017, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for EIF2AK4 were set to 25512148; 25917481; 24135949; 24292273; 27809840; 26320113;26387786

14 Jun 2017, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for EIF2AK4 were set to Pulmonary venoocclusive disease 2, 234810; PVOD; pulmonary capillary hemangiomatosis; PCH; Heritable pulmonary arterial hypertension; HPAH; Pulmonary arterial hypertension

9 Jun 2017, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for EIF2AK4 were set to 25512148; 25917481; 24135949; 24292273; 27809840;26320113

9 Jun 2017, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for EIF2AK4 were set to Pulmonary venoocclusive disease 2, 234810;Heritable pulmonary arterial hypertension;HPAH;Pulmonary arterial hypertension

9 Jun 2017, Gel status: 2

Gene classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

This gene has been classified as Amber List (Moderate Evidence).

9 Jun 2017, Gel status: 0

Set Mode of Inheritance

Louise Daugherty (Genomics England Curator)

Mode of inheritance for EIF2AK4 was changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

9 Jun 2017, Gel status: 0

Set publications

Louise Daugherty (Genomics England Curator)

Publications for EIF2AK4 were set to 25512148; 25917481; 24135949; 24292273;27809840

9 Jun 2017, Gel status: 0

Added New Source

Louise Daugherty (Genomics England Curator)

EIF2AK4 was added to Pulmonary arterial hypertensionpanel. Sources: Literature

9 Jun 2017, Gel status: 0

Created

Louise Daugherty (Genomics England Curator)

EIF2AK4 was created by LouiseD