Introduction. Shwachman-Diamond Syndrome (SDS) is an autosomal-recessive disorder characterized by neutropenia, pancreatic exocrine insufficiency, skeletal dysplasia, and an increased risk for leukemic transformation. Biallelic mutations in the SBDS gene have been found in about 90% of patients. The clinical spectrum of SDS in patients is wide, and variability has been noticed between different patients, siblings, and even within the same patient over time. Herein, we present two SDS siblings (UPN42 and UPN43) carrying the same SBDS mutations and showing relevant differences in their phenotypic presentation. Study aim. We attempted to understand whether other germline variants, in addition to SBDS, could explain some of the clinical variability noticed between the siblings. Methods. Whole-exome sequencing (WES) was performed. Human Phenotype Ontology (HPO) terms were defined for each patient, and the WES data were analyzed using the eVai and DIVAs platforms. Results. In UPN43, we found and confirmed, using Sanger sequencing, a novel de novo variant (c.10663G>A, p.Gly3555Ser) in the KMT2A gene that is associated with autosomal-dominant Wiedemann–Steiner Syndrome. The variant is classified as pathogenic according to different in silico prediction tools. Interestingly, it was found to be related to some of the HPO terms that describe UPN43. Conclusions. We postulate that the KMT2A variant found in UPN43 has a concomitant and co-occurring clinical effect, in addition to SBDS mutation. This dual molecular effect, supported by in silico prediction, could help to understand some of the clinical variations found among the siblings. In the future, these new data are likely to be useful for personalized medicine and therapy for selected cases.

The present clinical study was approved by the Review Board for Animals Care of the University of Parma prot N. 03/CESA /2023, which provided a consent to the clinical study: regulation (EU) no. 536/2014. (22A01712) (GU General Series n.65 of 18-03-2022); European Law (O.J. of E.C. L 358/1 12/18/1986), and USA Laws (Animal Welfare Assurance No A5594-01, Department of Health and Human Services, USA). The owners signed a voluntary informed consent form prior to the dogs’ enrollment in the study. Twenty female dogs, aged 1±1.5 months, and weighing 16± 0.5 kg were enrolled in the study. The inclusion criterion of the patients was to undergo ovariectomy surgery; dogs enrolled in this study had normal physiological, haematological and biochemical parameters.

Background. Sudden death is the leading cause of mortality in medically refractory cases of epilepsy. Younger persons with epilepsy (PWE), particularly those <40 years, have higher all-cause mortality than those without. However, data are conflicting about mortality and burden of cardiovascular disease (CVD) in middle-aged PWE. Objective: Determine all-cause and sudden death-specific mortality and burden of CVD in PWE in a middle-aged population. Methods. Using UK Biobank, we identified 7,786 (1.6%) participants with a diagnosis of epilepsy; 566 individuals with prior history of stroke were excluded. The 7,220 PWE comprised the study cohort with the remaining 494,676 without epilepsy as the comparator group. PWE were identified based on clinical diagnostic code (validated) or self-reported diagnosis at assessment centre interview. Prevalence of CVD was determined using validated diagnostic codes. Cox proportional hazards regression were used to assess all-cause mortality and sudden death risk, in PWE vs those without epilepsy. Results. Hypertension, coronary artery disease, heart failure, valvular heart disease, and congenital heart disease were all more prevalent in PWE. Arrhythmias including atrial fibrillation/flutter (12.2% vs 6.9%; p<0.01), bradyarrhythmias (7.7% vs 3.5%; p<0.01), conduction defects (6.1% vs 2.6%; p<0.01), and ventricular arrhythmias (2.3% vs 1.0%; p<0.01), as well as cardiac implantable electric devices (4.6% vs 2.0%; p<0.01) were all more common in PWE compared to comparator group. PWE had higher all-cause mortality (HR 3.9 [95% CI, 3.01-3.39]), higher sudden death-specific mortality (HR 6.65 [95% CI, 4.53-9.77]) both adjusted for age, sex and comorbidities; and were almost 2 years younger at death [68.1 vs 69.8; p<0.001]. Conclusions. PWE have markedly higher burden of CVD including arrhythmias and heart failure. Middle-aged PWE have increased all-cause and sudden death specific mortality and higher burden of CVD. While efforts have focused on SUDEP in the young, further work is required to elucidate mechanisms underlying all-cause mortality and sudden death risk in PWE of middle age, to identify prognostic biomarkers and develop preventative therapies in PWE.