Background Individuals harbouring SMAD3 pathogenic variants are at risk for aneurysms/dissections throughout the arterial tree. Based on prior reports of sex differences in thoracic aortic aneurysm/dissection, we investigated the sexual dimorphism for vascular events in SMAD3- variant-harbouring patients. Methods We analysed two large pedigrees comprising 84 individuals segregating pathogenic missense variants affecting the same p.Arg287 residue in SMAD3 . We excluded individuals<40 years without vascular involvement, as they were too young to be classified. Individuals were subcategorised according to sex, the presence or absence and localisation (aneurysm/dissection with or without involvement of the aortic root/ascending aorta) of vascular lesions. We complemented our familial patient cohort with 178 SMAD3 patients reported in the literature between 2011 and 2023. Results In our two pedigrees, 11/30 (37%) variant-harbouring females had no vascular involvement, whereas none of the va

We begin 2025 by looking back at the contribution of Charis Eng, a distinguished cancer geneticist and former North American editor of the Journal of Medical Genetics ( JMG ). In this issue, readers will find an obituary written by former coeditors and colleagues.1 In addition, the second invited commentary in our Six at Sixty series2 focuses on a paper coauthored by Charis Eng and published in JMG in 2005.3 This study reported …

Background We aimed to estimate real-world evidence of the prevalence rate of genetic developmental and epileptic encephalopathies (DEEs) in the Italian population over a 11-year period. Methods Fifteen paediatric and adult tertiary Italian epilepsy centres participated in a survey related to 98 genes included in the molecular diagnostic workflows of most centres. We included patients with a clinical diagnosis of DEE, caused by a pathogenic or likely pathogenic variant in one of the selected genes, with a molecular diagnosis established between 2012 and 2022. These data were used as a proxy to estimate the prevalence rate of DEEs. Results We included 1568 unique patients and found a mean incidence proportion of 2.6 patients for 100.000 inhabitants (SD=1.13) with consistent values across most Italian regions. The number of molecular diagnoses showed a continuing positive trend, resulting in more than a 10-fold increase between 2012 and 2022. The mean age at molecular diagnosis was 11.2

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are imprinting disorders caused by genetic or epigenetic aberrations of 15q11.2-q13. Their clinical testing is often multitiered; diagnostic testing begins with methylation-specific multiplex ligation-dependent probe amplification or methylation-sensitive PCR and then proceeds to molecular subtyping to determine the mechanism and recurrence risk. Currently, correct classification of a proband’s PWS/AS subtype often requires parental samples, a costly process for families and health systems. The use of nanopore sequencing for molecular diagnosis of PWS and AS has been explored by Yamada et al ; however, to confirm heterodisomy parental data were still required. Here, we investigate genome-wide nanopore sequencing in a larger cohort of PWS (18) and AS (6) as a singular test to detect the molecular subtype, without parental data. We accurately subtyped these cases including uniparental heterodisomy, mixed iso-/heterodisomy, type 1 and