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Rett syndrome (RTT) is a severe neurodevelopmental disorder, with MECP2 mutations accounting for 90–95% of classic and 50–70% of atypical cases. However, many clinically diagnosed RTT patients remain without molecular diagnoses. While point mutations and large rearrangements in MECP2 are well studied, the role of small-intermediate structural variants (SVs) remains mostly elusive. Using standard short-read whole genome sequencing, we identified novel de novo SVs in three out of three previously unresolved RTT cases: a complex SV with two deletions ( ~ 5Kbp and ~60Kbp) and a ~105Kbp inversion; a ~200Kbp translocation; and a ~3Kbp deletion. These findings suggest that such elusive SVs might be a common cause for “ MECP2 -negative” RTT. Incorporating SV detection into routine genetic testing through bioinformatic analysis of short-read sequencing or manual review using IGV could improve diagnostic rates and expand our understanding of RTT and similar disorders.

Oro-Facial-Digital Syndrome (OFDS) and Joubert syndrome are ciliary disorders. Fifteen individuals of consanguineous Bedouin kindred presented with global developmental delay with no speech, and a clear OFDS phenotype, combined with Joubert syndrome, with MRI showing hypoplastic corpus callosum and molar tooth sign. Renal and liver function tests and ultrasound were unremarkable. Within a 0.5 Mb disease-associated locus (LOD score 6.2), whole genome sequencing identified a single variant: CEP83 NG_051825.2:g.5774dupG, (NM_016122.3):c.-278dupG. Patient fibroblasts showed aberrantly long cilia, and alternative splicing of CEP83 5’UTR, skipping most of exon 1 of the canonical transcript, and frameshift, abrogating CEP83 mRNA and protein expression. CEP83 acts in primary cilium assembly. CEP83 biallelic missense or in-frame deletions, with presumed residual function, were previously associated with early-onset nephronophthisis culminating in end-stage renal disease. We now demonstrate that a biallelic complete loss-of-function CEP83 variant culminates in elongated primary cilia, causing OFDS with Joubert-like features without evident renal involvement.

With the increasing importance of genomic data in understanding genetic diseases, there is an essential need for efficient and user-friendly tools that simplify variant analysis. Although multiple tools exist, many present barriers such as steep learning curves, limited reference genome compatibility, or costs. We developed VARista, a free web-based tool, to address these challenges and provide a streamlined solution for researchers, particularly those focusing on rare monogenic diseases. VARista offers a user-centric interface that eliminates much of the technical complexity typically associated with variant analysis. The tool directly supports VCF files generated using reference genomes hg19, hg38, and the emerging T2T, with seamless remapping capabilities between them. Features such as gene summaries and links, tissue and cell-specific gene expression data for both adults and fetuses, as well as automated PCR design and integration with tools such as SpliceAI and AlphaMissense, enable users to focus on the biology and the case itself. As we demonstrate, VARista proved effective in narrowing down potential disease-causing variants, prioritizing them effectively, and providing meaningful biological context, facilitating rapid decision-making. VARista stands out as a freely available and comprehensive tool that consolidates various aspects of variant analysis into a single platform that embraces the forefront of genomic advancements. Its design inherently supports a shift in focus from technicalities to critical thinking, thereby promoting better-informed decisions in genetic disease research. Given its unique capabilities and user-centric design, VARista has the potential to become an essential asset for the genomic research community. https://VARista.link

Hypertrophic and dilated cardiomyopathy (HCM, DCM) are leading causes of cardiovascular morbidity and mortality in children. The pseudokinase alpha-protein kinase 3 (ALPK3) plays an essential role in sarcomere organization and cardiomyocyte differentiation. ALPK3 coding mutations are causative of recessively inherited pediatric-onset DCM and HCM with variable expression of facial dysmorphism and skeletal abnormalities and implicated in dominantly inherited adult-onset cardiomyopathy. We now report two variants in ALPK3 —a coding variant and a novel intronic variant affecting splicing. We demonstrate that compound heterozygosity for both variants is highly suggestive to be causative of infantile-onset HCM with webbed neck, and heterozygosity for the coding variant presents with adult-onset HCM. Our data validate partial penetrance of heterozygous loss-of-function ALPK3 mutations in late-onset hypertrophic cardiomyopathy and expand the genotypic spectrum of autosomal recessive ALPK3 -related cardiac disease with Noonan-like features. Graphical Abstract

Background: Home rehabilitation improves patient satisfaction and reduces the need for specialist consultations. Hemodialysis is a costly post-ICU service that requires frequent monitoring. Previous studies have demonstrated the feasibility and accuracy of patients self-scanning their lungs with an ultrasound device within the hospital. Methods: In this single-center, prospective pilot study, we compared the quality of high-risk elderly patient-generated lung ultrasound images against physician-generated images as our primary outcome. The secondary outcome assessed image quality and B-line quantification between a home device and a gold standard device, when operated by the same clinician. Results: We enrolled nine participants (66% male, median age 76 years [IQR 66,79]). Analysis included 402 ultrasound clips (163 patient-generated, 239 physician-generated, and 237 in-clinic gold standard clips). Patient-generated images demonstrated high reliability (92% highly reliable or reliable) and were non-inferior to physician-generated images (p < 0.001). There was substantial agreement in B-line classification (Kw = 0.64, 95% CI: 0.46–0.82). The home device, when operated by the same physician, showed non-inferiority to the gold standard device (p < 0.001) with substantial B-line classification agreement (Kw = 0.64, 95% CI: 0.51–0.78). Conclusions: High-risk elderly patients can successfully generate self-scanned lung ultrasound images comparable to those produced by physicians. These promising results warrant further investigation through larger-scale and long-term studies.