When "loss-of-function" means proteostasis burden: Thinking again about coding DNA variants.

Each human genome has approximately 5 million DNA variants. Even for complete loss-of-function variants causing inherited, monogenic diseases, current understanding based on gene-specific molecular function does not adequately predict variability observed between people with identical mutations or fluctuating disease trajectories. We present a parallel paradigm for loss-of-function variants based on broader consequences to the cell when aberrant polypeptide chains of amino acids are translated from mutant RNA to generate mutated proteins.

Acute endothelial stresses identify microRNA let-7b-5p and non-coding SLC11A2 (NRAMP2/DMT1) exon as biomarkers that overlap with those detected in malignant and non-malignant diseases.

Background: Disease biomarkers are often identified long after initiating pathologies, hampering mechanistic understanding and development of preventative strategies. We hypothesised that aberrant cellular responses to normally-encountered stresses may be relevant to later disease states.

Aim: To model two under-explored acute cellular stresses for blood-exposed cells, and cross-reference to known biomarkers of disease.

Alterations in Mitochondrial Function in Pulmonary Vascular Diseases.

Alterations of mitochondrial bioenergetics and arginine metabolism are universally present and mechanistically linked to pulmonary arterial hypertension (PAH), but there is little knowledge of arginine metabolism and mitochondrial functions across the different pulmonary hypertension (PH) groups. We hypothesize that abnormalities in mitochondrial functions are present across all PH groups and associated with clinical phenotypes. We test the hypothesis in PH patients and healthy controls from the Pulmonary Vascular Disease Phenomics Program cohort, who had comprehensive clinical phenotyping and follow-up for at least 4 years for death or transplant status.

Adaptation of ACMG/AMP guidelines for clinical classification of variants in Pulmonary Arterial Hypertension resolves variants of unclear pathogenicity in ClinVar.

Purpose: Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by pathogenic variants, most frequently in the bone morphogenetic protein receptor type 2 ( ) gene. We formed a ClinGen variant curation expert panel to devise guidelines for the clinical interpretation of variants identified in PAH patients.

Methods: The general ACMG/AMP variant classification criteria were refined for PAH and adapted to following ClinGen procedures.