Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta (TGF-β) pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II-like 1 (ACVRL1), endoglin (ENG) and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next-generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, maintenance and pathogenetic transformation of the pulmonary vascular bed. Together, these analyses represent the largest comprehensive compilation of BMPR2 and associated genetic risk factors for PAH, comprising known and novel variation. Additionally, with the inclusion of an allelic series of locus-specific variation in BMPR2, these data provide a key resource in data interpretation and development of contemporary therapeutic and diagnostic tools.

231tures which suggest pulmonary veno-occlusive disease or pulmonary hemosiderosis. 1,6 Furthermore, most patients with symptomatic PAH are not referred for lung biopsy due to risk of the procedure, unless there P ulmonary capillary hemangiomatosis (PCH) is a rare disease characterized by a proliferation of multiple layers of capillaries that expand alveolar septa and often invade bronchial walls and the pleura. 1 The disorder is slowly progressive and ultimately fatal. A trial of antiangiogenic therapy followed by lung transplantation is often offered to affected individuals. 2,3 Symptoms, including progressive dyspnea, cough, hemoptysis, fatigue, and weight loss, are not specifi c and mimic other forms of pulmonary arterial hypertension (PAH). Echocardiography and cardiac catheterization may suggest PAH or pulmonary veno-occlusive disease, 4,5 and the diagnosis may prove diffi cult because pathologic examination of lung tissue may show feaBackground: Pulmonary capillary hemangiomatosis (PCH) is a rare disease of capillary proliferation of unknown cause and with a high mortality. Families with multiple affected individuals with PCH suggest a heritable cause although the genetic etiology remains unknown. Methods: We used exome sequencing to identify a candidate gene for PCH in a family with two affected brothers. We then screened 11 unrelated patients with familial (n 5 1) or sporadic (n 5 10) PCH for mutations. Results: Using exome sequencing, we identifi ed compound mutations in eukaryotic translation initiation factor 2 a kinase 4 ( EIF2AK4 ) (formerly known as GCN2 ) in both affected brothers. Both parents and an unaffected sister were heterozygous carriers. In addition, we identifi ed two EIF2AK4 mutations in each of two of 10 unrelated individuals with sporadic PCH. EIF2AK4 belongs to a family of kinases that regulate angiogenesis in response to cellular stress. Conclusions: Mutations in EIF2AK4 are likely to cause autosomal-recessive PCH in familial and some nonfamilial cases. CHEST 2014; 145(2):231-236Abbreviations: EIF2AK4 5 eukaryotic translation initiation factor 2 a kinase 4; IRB 5 institutional review board; PAH 5 pulmonary arterial hypertension; PCH 5 pulmonary capillary hemangiomatosis

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