Whole Exome Sequence Analysis Provides Novel Insights into the Genetic Framework of Childhood-Onset Pulmonary Arterial Hypertension

Figures

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  Figure 1. Sequence chromatograms and familial segregation of identified variants in childhood-onset pulmonary arterial hypertension (cPAH). (A) Patient 1 has a c.1148C>A missense mutation in ATP13A3; (B) Patient 2 has a heterozygous BMP10 c.247G>A mutation; (C) Patient 3 is heterozygous for a c.550G>A mutation in PDGFD; (D) Patient 4 has a c.1069G>A missense variant in the ABCC8 gene; (E) Patient 5 carries a heterozygous SMAD9 c.1117G>A missense variant, which co-segregates with the disease (+/−) in his affected mother and maternal grandfather, who is an obligate carrier. Unaffected family members available for testing are all wild-type (WT). The horizontal line underlines the mutated codon. * DNA sample not available.

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  Figure 2. Protein structure of ATP13A3 highlighting mutations identified in PAH. Topological analysis of ATP13A3 according to UniProtKB protein component and site position data (ID: Q9H7F0) and published reports [38,40]. Likely pathogenic PAH mutations (CADD ≥ 15) reported in the literature are indicated by the filled grey circles [10,12,20,41]. The c.1148C>A (p.T383K) mutation identified in this study is highlighted by the gold star and is located adjacent to a previously reported splice-region variant [10]. Numbers indicate amino acid positions at each end of the 10 transmembrane domains. The red triangles denote essential asparagine residues (D498: active catalytic site; D883, D887: Mg2+ binding sites). A domain: actuator domain; C: carboxyl terminus; N domain: nucleotide binding domain; NH2: amino terminus; P domain: phosphorylation domain.