The Canary Islanders exhibit a unique genetic admixture, comprising European (EUR), North African (NAF), and sub-Saharan African (SSA) ancestries. We comprehensively characterized the full spectrum of small genetic variation in this population based on whole-exome sequencing data to further develop CIRdb. Our results revealed 387,555 variants, of which 15.1% were previously unreported, and we prioritized novel putative pathogenic variants exhibiting enrichment in respiratory, cardiovascular, and metabolic disorders. Genetic differentiation patterns provided fine-grained insights into within-archipelago differentiation. We revealed an EUR genetic ancestry enrichment around the 17q21.31 inversion (a pleiotropic locus associated with pulmonary, infectious, and immunological diseases) and a candidate selective sweep shared by Canary Islanders and the NAF population around prune exopolyphosphatase 1 (PRUNE1) gene, which is associated with body mass index, cardiovascular health, and metabolic and respiratory traits. Taken together, our findings show that CIRdb presents a valuable resource of exome-wide genetic variation in a population at the edge of Southwestern European genetic diversity.
Hereditary angioedema is a rare, autosomal dominant, genetic disorder characterized by recurrent episodes of angioedema. Over 800 SERPING1 gene variants have been reported, and their clinical profiles and causal genetic variants are highly heterogeneous. We report two cases of hereditary angioedema (HAE) in a Portuguese family: a 27-year-old male, under lanadelumab, and his 57-year-old father, kept on on-demand treatment. Genetic testing was performed following international guidelines. The Hereditary Angioedema Database Annotation highlighted a heterozygous insertion at exon 3 (c.336_337insC). This variant predicts a frameshift of the transcript, with the introduction of a premature STOP codon in C1-INH protein (p.Ser113LeufsTer20). We report the identification of a novel pathogenic SERPING1 variant in a family with HAE type 1, assisted by the Hereditary Angioedema Database Annotation variant prioritization tool. Our results may contribute to the identification of additional families with the same variant and can further enhance the knowledge about this condition.
Introduction: Corticosteroids (CS) improve survival in severe infections, but variable responses have been reported. We aimed to identify genetic variants that could be associated with the differential CS response. Methods: We performed a genome-wide association study (GWAS) of 90day mortality in a cohort of hospitalized COVID-19 patients treated with CS from the SCOURGE consortium (Ncases=375, Ncontrols=1,850). Logistic regression models were conducted in ∼9.5M TOPMed-imputed variants (significance set at p=5x10-8). Then, we tested the polygenic overlap of the CS response between COVID-19 and all-cause sepsis using PRSice-2 to perform polygenic risk scores (PRS). The PRS were tested on the independent CS-treated all-cause sepsis patients (Ncases=21, Ncontrols=69) from the GEN-SEP cohort. The best PRS model was subject to pathway-specific PRS studies using PRSet to evaluate which pathways were related to the differential CS response. Results: Three PLCG2 variants, two intronic and one in the 3’-UTR region, were associated with CS response in COVID-19 (plowest=2.79x10−8). A PRS model including 31,374 variants reaching a pthreshold=0.0298 in the GWAS was nominally associated with CS response among all-cause sepsis patients (p=0.044). Pathway-specific PRS analyses revealed the regulation of the cholesterol biosynthesis pathway as the most significantly associated with CS response in all-cause sepsis (p=0.001). Conclusions: Overlapping polygenic effects of the CS response between COVID-19 and all-cause sepsis were observed. Genetic variants affecting the regulation of cholesterol biosynthesis pathway could underlie the CS response differences during critical illness.
Background: Idiopathic pulmonary fibrosis (IPF) is a rare disease with a poor prognosis. Disease risk involves rare and common genetic variants. However, an inverse association have been described between them. Accordingly, IPF patients with a higher polygenic risk score (PRS) for IPF are less likely to carry rare deleterious variants and vice versa. Here, we evaluate weather PRS of IPF could serve as an additional criterion to patient prioritisation for rare variant discovery. Methods: We identified carriers based on the presence of rare qualifying variants (QVs) in genes linked to monogenic forms of pulmonary fibrosis in 888 IPF patients from the Pulmonary Fibrosis Foundation Patient Registry (PFFPR). Genome-wide association study (GWAS) summary statistics from independent cohorts were used to construct a whole-genome PRS (WG-PRS) using a clumping and thresholding method (C+T) and a Bayesian method (SBayesRC). PRS were also derived from 19 known common sentinel IPF variants (Sentinel-PRS). Logistic regression models were used to evaluate associations between PRS and carrier status. Discriminatory performancewas evaluated using area under the curve (AUC) analysis, and comparisons were made with DeLong’s test. Validation was performed in 472 IPF individuals from the UK PROFILE cohort. Findings: IPF-PRS were strongly associated with the QVs carrier status: Odds Ratio [OR] 0.65 (95% Confidence Interval [CI] 0.53-0.79) for WG-PRSC+T, OR 0.71 (95% CI 0.59-0.86) for WG-PRSSBayesRC, and OR 0.77 (95% CI 0.63-0.94) for Sentinel-PRS. Adding WG-PRS to the patient’s personal clinical history improved the prediction of QVs carriers: AUC=0.62 for the clinical model, AUC=0.68 for WG-PRSC+T (DeLong’s test, p=9.54x10-4) and AUC=0.66 for WG-PRSSBayesRC (DeLong’s test, p=0.02). Adding of IPF-PRS to clinical variables correctly reclassified 22.8% of carriers when using WG-PRSC+T, 20.8% when using Sentinel-PRS, and 16.7% for WG-PRSSBayesRC. WG-PRSSBayesRC and the Sentinel-PRS also demonstrated improved prediction of QVs carriers in telomere-related genes in PROFILE. Interpretation: Incorporating IPF-PRS into a model based on the patient’s clinical history improves the identification of QVs carriers. Although the overall discriminatory power was moderate, these findings raise de the possibility of using WG-PRS as useful criterion for rare variant discovery in patients with IPF and enhance decision-making.
Background Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent edema attacks mediated by bradykinin dysregulation. While SERPING1 and F12 account for most of cases worldwide, genetic causes in a significant proportion of patients are unknown, particularly in patients with normal C1 inhibitor plasmatic levels (HAE-nC1INH). Methods We performed whole-exome sequencing (WES) on 102 families from insular Portugal and Spain and established a sequential variant prioritization strategy combining the HADA tool with a virtual panel of genes linked to the kinin-kallikrein (KKS) and complement pathways. Results We identified 28 pathogenic/likely pathogenic variants, including seven novel SERPING1 variants and two novel F12 variants. In the cases lacking genetic alterations in established HAE genes, candidate variants were prioritized in KKS genes with the potential to explain the disease. Genetic testing of relatives beyond index cases improved diagnostic yield (88.3% in multiplex families vs. 21.1% in proband-only cases) despite functional studies are required to validate the effects of prioritized variants. Conclusion Our study expands the mutational spectrum of HAE, proposes novel candidate variants in genes interacting with the classical bradykinin pathway and reinforces the need of genetic tests as first level diagnostic tool to reduce diagnostic delays and the precise management of HAE patients.
