Gene panel diagnostics reveals new pathogenic variants in pulmonary arterial hypertension

Figures

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  Fig. 1. Flow chart of variant characterization process. Variants were firstly characterised by their population frequency in the genome aggregation database (GnomAD). Those with a frequency above 0.5% were excluded from further analysis. Secondly, all available evidence for each variant was taken into consideration to obtain a final classification. Likely pathogenic and pathogenic variants were termed “mutations”

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  Fig. 2. Distribution of mutations across genes. The majority of mutations (65%) was identified in the BMPR2 gene. The remaining variants were found in 10 further PAH genes. Six large deletions or duplications in the BMPR2 gene were identified in nine patients using multiplex ligation-dependent amplification (MLPA)

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  Fig. 3. Pedigrees of three non-BMPR2 families. a Pedigree of AQP1 family. The index patient and his uncle carried the heterozygous missense mutation in exon 1 of the gene AQP1 X1 c.376C > T p.(Arg126Cys). The brother and father of the index patient had died of PAH. No further samples were available from the family. b Pedigree of SOX17 family. The familial heterozygous missense mutation was located in exon 2 of the gene SOX17 c.413G > C p.(Arg138Pro). It was prevalent in all three siblings and cousin of the index with PAH, while being absent in the only healthy sibling of the index patient. c Pedigree of KCNK3 family. Both parents were heterozygous for the 18 bp duplication in exon 1 c.250_267dup p.(Val84_Thr89dup) displayed in grey. Downstream to the left are the same 18 bp present in the wild-type reference sequence. Both children developed PAH and were homozygous for the duplication. Filled symbol: PAH, empty symbol: healthy family member; the number within the symbols is current age or age at death, Dx: age at diagnosis; upper sequence: wild type reference sequence, bottom sequence: sequence of family member; grey: duplicated sequence not present in the wild-type reference sequence