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EIF2AK4 mutation as "second hit" in hereditary pulmonary arterial hypertension
Christina A Eichstaedt1,2,3, Jie Song1,2,3, Nicola Benjamin1,3
1Center for Pulmonary Hypertension at the Thoraxclinic, University Hospital Heidelberg, Heidelberg, 69126, Germany.
Mutations in the EIF2AK4 gene, previously linked to recessive disease, are now associated with autosomal dominant pulmonary arterial hypertension (HPAH). Co-occurrence of EIF2AK4 and BMPR2 mutations explains incomplete HPAH penetrance.
Area of Science:
- Genetics
- Cardiology
- Pulmonary Medicine
Background:
- Mutations in EIF2AK4 are linked to recessively inherited veno-occlusive disease.
- This study investigates EIF2AK4 mutations in autosomal dominantly inherited pulmonary arterial hypertension (HPAH) with incomplete BMPR2 mutation penetrance.
Purpose of the Study:
- To determine if EIF2AK4 mutations contribute to HPAH in a family with incomplete BMPR2 mutation penetrance.
- To explore the genetic basis of variable HPAH manifestation within families.
Main Methods:
- Clinical examinations including echocardiography and lung function tests were performed on 10 family members.
- Next-generation sequencing PAH gene panel analysis identified variants, confirmed by Sanger sequencing.
Main Results:
- All affected HPAH family members carried compound heterozygous mutations in BMPR2 and EIF2AK4.
- Family members with only a BMPR2 mutation did not develop manifest HPAH.
Conclusions:
- EIF2AK4 mutations can contribute to autosomal dominant HPAH, not just recessive forms.
- The co-occurrence of EIF2AK4 and BMPR2 mutations supports a "second hit" hypothesis for HPAH penetrance.
- Genetic analysis of all known PAH genes aids in predicting HPAH clinical outcomes.
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