The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members

Heart Failure and Epicardial Adipose Tissue

Epicardial adipose tissue (EAT) has been investigated in patients with both systolic and diastolic heart failure and suggested to play a pathogenic role, although results are not univocal. Experimental studies suggest a potential protective role of the brown fat features of EAT against the systolic heart failure. A function of EAT p53 and adiponectin has been also suggested in patients with heart failure. A neuromodulatory role of EAT in heart failure has been also considered. Clinically, diastolic heart failure is commonly associated with higher EAT. The role of EAT in the systolic heart failure is more controversial, as it could be influenced by concomitant confounders, such as coronary artery disease, diabetes and obesity. Some studies found that EAT volume was higher in patients with systolic heart failure, whereas other studies showed that either CT, MRI or ultrasound measured epicardial fat was actually lower in subjects with systolic heart failure. Epicardial fat may incur in fibrotic changes during chronic and advanced cardiac failure. Whether EAT plays a role in the long-term prognosis of heart failure requires future investigation