The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.

Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.

Improvement of non-adherence and reduction of BP values in patients with difficult-to-treat hypertension: the ATHAN clinical trial.

Hypertension treatment and blood pressure (BP) control reduce cardiovascular disease burden. However, prevalence of controlled BP is overall insufficient and lack of adherence to treatment is a suggested major contributor. This prospective, randomized clinical trial was designed to evaluate whether a specific 3-month (m) action plan to improve therapeutic adherence results in a decrease in BP. Patients with ambulatory 24 h-BP ≥ 130/80 mmHg despite receiving ≥2 antihypertensive drugs and with therapeutic non-compliance confirmed by antihypertensive drugs analyzed in urine were randomized (1:1) to receive a specific 3 m program to improve adherence (INT = intervention) or routine follow-up (C = control). Antihypertensive treatment was not modified and knowledge of non-adherence was only notified to patients randomized to the intervention group. Before randomization and at 3 m all patients underwent urinary screening for antihypertensive drugs and 24 h-ambulatory-BP monitoring. Forty-five patients (36% women, mean age: 58 ± 13 yr) were randomized. At 3 m, mean (95% CI) BP differences (INT vs. C) were 12.2 mmHg (4.3-20.8), adjusted-p = 0.032 and 8.7 mmHg (2.5-14.8), adjusted-p = 0.018 for 24 h-systolic and 24 h-diastolic BP, respectively. Differences (INT vs. C) for office SBP and DBP were 18.4 mmHg (6.8-30.1), adjusted-p = 0.005 and 15.7 mmHg (7.2-24.2), adjusted-p < 0.001. Non-detected antihypertensive drugs were median [IQR]: 40% [25-100] and 0% [0-20] at baseline and 3 m, respectively, in the INT group, and 33.3% [25-63.7] and 33.3% [23.8-57.9], in the C group (p < 0.001 for the 3-month between-group comparison). A combined action plan of notifying knowledge of non-adherence plus a 3-month specific nursing intervention to improve therapeutic adherence results in BP reduction in patients with inadequate therapeutic compliance.