Seven Additional Patients with SOX17 Related Pulmonary Arterial Hypertension and Review of the Literature

Abstract

Pulmonary arterial hypertension (PAH) is an infrequent disorder characterized by high blood pressure in the pulmonary arteries. It may lead to premature death or the requirement for lung and/or heart transplantation. Genetics plays an important and increasing role in the diagnosis of PAH. Here, we report seven additional patients with variants in SOX17 and a review of sixty previously described patients in the literature. Patients described in this study suffered with additional conditions including large septal defects, as described by other groups. Collectively, sixty-seven PAH patients have been reported so far with variants in SOX17, including missense and loss-of-function (LoF) variants. The majority of the loss-of-function variants found in SOX17 were detected in the last exon of the gene. Meanwhile, most missense variants were located within exon one, suggesting a probable tolerated change at the amino terminal part of the protein. In addition, we reported two idiopathic PAH patients presenting with the same variant previously detected in five patients by other studies, suggesting a possible hot spot. Research conducted on PAH associated with congenital heart disease (CHD) indicated that variants in SOX17 might be particularly prevalent in this subgroup, as two out of our seven additional patients presented with CHD. Further research is still necessary to clarify the precise association between the biological pathway of SOX17 and the development of PAH.

Keywords: SOX17; cardiovascular disorders; congenital heart disease; genomic medicine; personalized medicine; pulmonary arterial hypertension; whole exome sequencing.

Figure 1

Description of the total cohort analyzed in this study.

Figure 2

(A) Workflow for single nucleotide variant and insertion-deletions variant prioritization. Schematic representation of the pipeline for tertiary/prioritization analysis. BAM review was performed through Alamut and IGV; splicing analysis was performed through SpliceSiteFinder-like, MaxEntScan, GeneSplicer, and NNSPLICE. (B) Workflow for copy number variant prioritization. #Samples: Patients were divided into different work pools (minimum 20 patients) and analyzed in the same project. In this filter it is specified that the variant has to be found in 5 or less patients of that pool.

Figure 3

Cardiac magnetic resonance imaging of the first patient. (A) A 4-chamber CINE image showing the predominant right chamber dilation as compared to the left ventricle; (B) a short-axis CINE sequence demonstrating the severe dilation of both ventricles, with a centered interventricular septum. Pericardial effusion could also be noted. RV: right ventricle; RA: right atrium; LV: left ventricle; RV: right ventricle.

Figure 4

Angiographic study of patient HTP973. (A) Subselective pulmonary angiography of the lower right anterior pulmonary trunk, showing generalized “corkscrew”, tortuous subsegmental vessels. (B,C) Computed tomography angiography images demonstrating the presence of “corkscrew” and tortuous arteries in both lungs, as well as subpleural vessels.

Figure 5

Proportion of variants detected in SOX17 according to the variant type in previously published patients and our cohort.

Figure 6

Amino acid sequence of HMG-box domain in SOX family. The SOX family is comprised of 20 members and is grouped based on domain organization. Each SOX family member contains a highly conserved HMG domain (in grey, the most conserver residues). Variants detected in SOX17 in PAH patients are shown in colors: green (missense), yellow (nonsense), and red (frameshift).

Figure 7

Summary and representation of the variants found in SOX17. (A) Schematic representation of the SOX17-encoded protein and location of genetic variants according to the effect of the variant in the protein; (B) linear schematic of the SOX17 gene.