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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Alport Syndrome is a progressive renal disease with cochlear and ocular involvement. The most common form (~80%) is inherited in an X-linked pattern. X-linked Alport Syndrome (XLAS) is caused by mutations in the type IV collagen alpha chain 5 (COL4A5). We have developed a curated disease-specific database containing reported sequence variants in COL4A5. Currently the database archives a total of 520 sequence variants, verified for their position within the COL4A5 gene and named following standard nomenclature. Sequence variants are reported with accompanying information on protein effect, classification of mutation vs. polymorphism, mutation type based on the first description in the literature, and links to pertinent publications. In addition, features of this database include disease information, relevant links for Alport syndrome literature, reference sequence information, and ability to query by various criteria. On-line submission for novel gene variants or updating information on existing database entries is also possible. This free online scientific resource was developed with the clinical laboratory in mind to serve as a reference and repository for COL4A5 variants.

Somatic PIK3CA mutations may relate to pathogenesis of isolated macrodactyly. We set up to test the association between PIK3CA mutations with isolated macrodactyly in order to establish a more accurate and molecular mechanism-based diagnosis and classification. DNA extracted from affected tissues in 12 individuals with isolated macrodactyly was tested for PIK3CA mutation using targeted Sanger DNA sequencing. Ten patients had macrodactyly in the foot and two in the hand. Nine of the 12 patients were found to carry a low-level, mosaic PIK3CA mutation. The mutations identified, p.His1047Arg, p.His1047Leu, p.Glu545Lys, and p.Glu542Lys, are codons frequently mutated in cancers. Among all tissues tested, adipose had the highest mutation detection rate, followed by nerve and skin. Our results indicate that a high proportion of isolated macrodactyly patients carry a pathogenic PIK3CA mutation. Affected adipose, nerve and skin tissues are ideal for PIK3CA mutation analysis.