Genotes - a 'just-in-time' genomics education resource co-designed with clinicians.

Background: Powerful new genomic technologies are transforming the way healthcare is delivered, shaping medical practice across all specialties. In this rapidly changing landscape, there is an urgent need to equip the clinical workforce with knowledge and skills to navigate the new healthcare terrain. Co-design of healthcare resources with end users is increasingly gaining traction as a method of ensuring that educational content and delivery are tailored to users' needs, increasing likelihood of use and resulting in better outcomes for patients.

Evaluation of the Master's in Genomic Medicine framework: A national, multiprofessional program to educate health care professionals in NHS England.

Purpose: Genomic medicine is revolutionizing health care but requires health care professionals to update their understanding of genomics and its application to clinical practice for successful implementation. To meet this need, Health Education England developed the Master's in Genomic Medicine, a national multiprofessional program to increase genomic literacy in the National Health Service workforce. This study summarizes an evaluation of the program, which will inform its future development.

Unraveling GRIA1 neurodevelopmental disorders: Lessons learned from the p.(Ala636Thr) variant.

Ionotropic glutamate receptors (iGluRs), specifically α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), play a crucial role in orchestrating excitatory neurotransmission in the brain. AMPARs are intricate assemblies of subunits encoded by four paralogous genes: GRIA1-4. Functional studies have established that rare GRIA variants can alter AMPAR currents leading to a loss- or gain-of-function.

Epilepsy and overgrowth-intellectual disability syndromes: a patient organization perspective on collaborating to accelerate pathways to treatment.

Overgrowth-intellectual disability (OGID) syndromes are a collection of rare genetic disorders with overlapping clinical profiles. In addition to the cardinal features of general overgrowth (height and/or head circumference at least two standard deviations above the mean) and some degree of intellectual disability, the OGID syndromes are often associated with neurological anomalies including seizures. In an effort to advance research in directions that will generate meaningful treatments for people with OGID syndromes, a new collaborative partnership called the Overgrowth Syndromes Alliance (OSA) formed in 2023.

Massive open online courses (MOOCs) in genomic variant interpretation: An innovative education strategy for the growing genetic counselor workforce.

The growth in genomic testing in healthcare requires a highly trained specialist workforce to ensure evidence based clinical germline variant interpretation. Genetic counselors form a core part of the clinical genomics multidisciplinary team (MDT) and represent a growing workforce participating in variant interpretation from data analysis to the patient consultation. Standardized, high-quality variant interpretation training for Genetic Counselors has historically been ad hoc and variable, with existing programs lacking capacity to reach the entire workforce.

A cross-professional competency framework for communicating genomic results.

To ensure genomic medicine is delivered safely and effectively, it is crucial that healthcare professionals are able to understand and communicate genomic results. This Education Innovation describes a nationally agreed, cross-professional competency framework outlining the knowledge, skills and behaviors required to communicate genomic results. Using principles of the nominal group technique, consensus meetings with clinical, scientific and educational experts identified six stages in the return of results process, drafted and iterated competencies.

Evaluation of two Massive Open Online Courses (MOOCs) in genomic variant interpretation for the NHS workforce.

Background: The implementation of the National Genomic Medicine Service in the UK has increased patient access to germline genomic testing. Increased testing leads to more genetic diagnoses but does result in the identification of genomic variants of uncertain significance (VUS). The rigorous process of interpreting these variants requires multi-disciplinary, highly trained healthcare professionals (HCPs).

Implementation of precision medicine in healthcare-A European perspective.

The technical development of high-throughput sequencing technologies and the parallel development of targeted therapies in the last decade have enabled a transition from traditional medicine to personalized treatment and care. In this way, by using comprehensive genomic testing, more effective treatments with fewer side effects are provided to each patient-that is, precision or personalized medicine (PM). In several European countries-such as in England, France, Denmark, and Spain-the governments have adopted national strategies and taken "top-down" decisions to invest in national infrastructure for PM.

The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients.

Potocki-Shaffer syndrome (PSS) is a rare neurodevelopmental disorder caused by deletions involving the 11p11.2-p12 region, encompassing the plant homeodomain finger protein 21A (PHF21A) gene. PHF21A has an important role in epigenetic regulation and PHF21A variants have previously been associated with a specific disorder that, whilst sharing some features of PSS, has notable differences.

Mainstreaming of genomics in oncology: a nationwide survey of the genomics training needs of UK oncologists.

Objective: Genomics is rapidly changing treatment paradigms for cancers, obligating oncologists to have good genomics knowledge. Through this survey, we aimed to assess the current understanding of cancer genomics among UK oncologists.

Methods: We conducted a web-based nation-wide self-assessment survey of the cancer genomics knowledge of UK clinical and medical oncology trainees and consultants.

ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients.

Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.

Purpose: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain.

Methods: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR).

Systematic Profiling of Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor.

Clonal hematopoiesis is a prevalent age-related condition associated with a greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A () are the most common driver of this state. variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations are unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated mutations, and found that 74% were loss-of-function mutations.

Whole-genome analysis as a diagnostic tool for patients referred for diagnosis of Silver-Russell syndrome: a real-world study.

Background: Silver-Russell syndrome (SRS) is an imprinting disorder characterised by prenatal and postnatal growth restriction, but its clinical features are non-specific and its differential diagnosis is broad. Known molecular causes of SRS include imprinting disturbance, single nucleotide variant (SNV), CNV or UPD affecting several genes; however, up to 40% of individuals with a clinical diagnosis of SRS currently receive no positive molecular diagnosis.

Methods: To determine whether whole-genome sequencing (WGS) could uncover pathogenic variants missed by current molecular testing, we analysed data of 72 participants recruited to the 100,000 Genomes Project within the clinical category of SRS.

Delineating the Smith-Kingsmore syndrome phenotype: Investigation of 16 patients with the MTOR c.5395G > A p.(Glu1799Lys) missense variant.

Smith-Kingsmore Syndrome (SKS) is a rare genetic syndrome associated with megalencephaly, a variable intellectual disability, autism spectrum disorder, and MTOR gain of function variants. Only 30 patients with MTOR missense variants are published, including 14 (47%) with the MTOR c.5395G>A p.

Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

Background: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings.

Methods: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals).

Early-Onset Parkinsonism Is a Manifestation of the PPP2R5D p.E200K Mutation.

PPP2R5D-related neurodevelopmental disorder is characterized by a range of neurodevelopmental and behavioral manifestations. We report the association of early-onset parkinsonism with the PPP2R5D p.E200K mutation.

A synonymous UPF3B variant causing a speech disorder implicates NMD as a regulator of neurodevelopmental disorder gene networks.

Loss-of-function mutations of the X-chromosome gene UPF3B cause male neurodevelopmental disorders (NDDs) via largely unknown mechanisms. We investigated initially by interrogating a novel synonymous UPF3B variant in a male with absent speech. In silico and functional studies using cell lines derived from this individual show altered UPF3B RNA splicing.

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism.