The aims of the study were to answer the questions: are there universal values for birth incidence and population prevalence for the rare neurodevelopmental condition Prader-Willi syndrome (PWS)? If so, why are published estimates so widely different? A review of the 11 published estimates revealed methodological flaws resulting in higher estimates. Consideration of characteristics of […]
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Location matters: topography of germline CEBPA variants predicts variable outcomes in familial acute myeloid leukaemia—a rare disease perspective (Contributed by Dr Jinjun Yang)
Familial acute myeloid leukemia (AML) caused by inherited CEBPA variants is traditionally considered a favorable-risk form of leukemia. However, by analyzing patients from our institution together with all previously reported families worldwide, we found that not all inherited CEBPA variants behave the same way. The location of the variant within the CEBPA gene strongly influenced […]
Evaluating consistency and variation in mainstream germline cancer genetic and genomic testing (Contributed by Dr Agnes Sebastian)
Mainstreaming—shifting genetic testing outside clinical genetics—can improve access, but requires evaluation to ensure consistent, high-quality care. This study assessed real-world implementation of mainstream cancer genetic testing across multiple centres and cancer types, incorporating both clinical and laboratory genetics perspectives. Practice was broadly aligned for common indications, including breast, ovarian, and prostate cancer. However, variability remained […]
Safety and Efficacy of AAV-based Mini- and Micro-Dystrophin Gene Therapies in Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis of Clinical Trials (Contributed by Dr Haya Nassour)
Duchenne muscular dystrophy is a genetic disease caused by pathogenic variants in the gene encoding dystrophin, a protein essential for muscle function, leading to progressive muscle weakness and loss of mobility. Several gene replacement therapies that use viral vectors to deliver shortened versions of the dystrophin gene are being tested in clinical trials. We reviewed […]
Field watch: AlphaGenome Atlas maps predicted effects of ~9 billion human SNVs
Google DeepMind has released the AlphaGenome Atlas, a large-scale resource containing precomputed predictions for nearly every possible single-nucleotide substitution in the human genome. The atlas extends the AlphaGenome framework to genome-wide variant interpretation, including predicted effects on gene expression, splicing, chromatin accessibility, and other regulatory features. The resource may be particularly useful for prioritizing noncoding […]
Phenotypic manifestations and variant reclassification of germline PTEN variants: a nationwide Danish study (Contributed by Annette Lyngholm Sandsdalen)
PTEN Hamartoma Tumor Syndrome (PHTS) is a hereditary syndrome defined by a pathogenic variant in the PTEN tumor suppressor gene. PHTS is rare and associated with an increased risk of different cancers, benign tumors, and neurological manifestations. Collaborating across all departments of clinical genetics in Denmark, we identified patients with PHTS and gathered information in […]
Exome sequencing and large-scale analysis of electronic medical record-linked biobank data identify candidate deafness genes (Contributed by Prof. Karen B. Avraham)
Hearing loss is often caused by genetic variants, but for many people, the underlying cause remains unknown, preventing an accurate diagnosis and limiting access to emerging genetic therapies. We performed whole-exome sequencing in more than 1,000 people with hearing loss and integrated the findings with data from their electronic medical records. Despite incomplete clinical information, […]
Exploring the clinical and mutational spectrum of MORC2-associated disorders (Contributed by Dr Aysylu Murtazina)
Pathogenic variants in the MORC2 gene cause two distinct conditions: Charcot–Marie–Tooth disease type 2Z, an isolated peripheral neuropathy, and DIGFAN syndrome, a more severe neurodevelopmental disorder with early onset. Analyzing our patients and previously described cases with early-onset phenotype, we show that DIGFAN syndrome can be stratified into two neurological subtypes: one predominantly neuromuscular, the […]
Field watch: Suppressor tRNA therapy rescues nonsense mutations
Chen et al. report in Science a nonviral strategy for treating cystic fibrosis caused by nonsense mutations. The team engineered suppressor tRNAs and delivered them to the lung using inhaled lipid nanoparticles. In CF bronchial cells, mouse models, and patient-derived organoids, the treatment enabled readthrough of premature stop codons and restored full-length CFTR protein and […]
Rapid minigene workflow for functional reclassification of splicing variants in hereditary cancer diagnostics (Contributed by Dr Noemi Calandra)
Genetic testing has transformed the diagnosis of hereditary cancer syndromes, but many DNA variants remain difficult to interpret because their biological effects are unknown. This uncertainty can complicate genetic counselling and clinical management. We developed a rapid functional test to experimentally determine whether suspected variants disrupt RNA splicing, the process by which RNA is edited […]