CACNA1C is known to be associated with arrhythmias and developmental disorders, while its role in epilepsy has remained unclear. In this study, we focused on CACNA1C mutations in focal epilepsy, one of the most common seizure types. Using trio-based whole-exome sequencing, we identified three de novo CACNA1C mutations in patients with focal epilepsy. Notably, we […]
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The British Society for Genetic Medicine guidance on managing incidental findings identified during rare disease genomic testing (Contributed by Dr Sian Ellard)
Genomic testing for people affected by rare diseases will occasionally identify a gene variant or other finding that is not related to the reason for testing. This guidance on managing such “incidental findings” has been developed to support the specialist genomics workforce within the national health services in the UK and Ireland. It describes the […]
Enrichment of an Ehlers-Danlos-like Phenotype in Women with the FMR1 Premutation: A Pilot Study (Contributed by Dr Emily L Casanova)
Women who carry the FMR1 premutation are known to be at risk for several fragile X-associated conditions, but connective tissue problems have received relatively little attention. In this pilot study, we found that women with the premutation were much more likely than expected to show features resembling hypermobile Ehlers-Danlos syndrome, including joint hypermobility, chronic pain, […]
Everolimus for the treatment of neuropsychological deficits in tuberous sclerosis complex: findings from the TRON multicentre randomised controlled trial (Contributed by Dr Julian R Sampson)
Tuberous sclerosis complex is a rare inherited condition that causes a combination of widespread tumours, epilepsy and neuropsychological problems including autism and learning difficulties. Everolimus is an effective drug for treating the tumours and epilepsy. This paper reports a clinical trial of twenty-four weeks of everolimus treatment compared with placebo (an identical appearing pill without […]
Single-cell transcriptomics identifies neural fate disruption and glial reprogramming caused by RARS2 deficiency (Contributed by Dr. Xing Wei)
Pontocerebellar hypoplasia type 6 is a severe childhood brain disorder caused by defects in genes important for mitochondrial function. In this study, we used zebrafish and single-cell RNA sequencing to understand how loss of RARS2 affects early brain development. We found that RARS2 deficiency damages mitochondrial structure, disrupts normal neuronal development, and promotes abnormal glial […]
Field watch: Human body single-cell atlas of three-dimensional genome organization and DNA methylation
A study published in Science presents a single-cell atlas of DNA methylation and three-dimensional genome organization across the human body. Zhou and colleagues profiled 86,689 nuclei from 16 adult tissues, characterizing 35 major cell types and 206 subtypes. Their findings reveal extensive cell type–specific differences in methylation, chromatin loops, and long-range genome organization, while showing […]
Potential advantage of clinical exome sequencing in BRCA1/2-negative families: a retrospective study of a cohort of 500 patients at a high-risk for hereditary cancers (Contributed by Dr. Federico Anaclerio)
Many families with a strong history of cancer remain without a genetic diagnosis after standard BRCA1/2 testing. In this study, we investigated whether Clinical Exome Sequencing (CES) could provide additional genomic information in 500 high-risk individuals who previously tested negative for BRCA1/2 pathogenic variants. While most additional findings are not yet ready for routine clinical […]
Cancer Variant Interpretation Group UK (CanVIG-UK): updates on an exemplar national subspecialty multidisciplinary network (Contributed by Dr. Alice Garrett and Sophie Allen)
Cancer Variant Interpretation Group UK (CanVIG-UK) was established in 2017. Its initial purpose was to improve consistency in the interpretation of genetic data from cancer susceptibility genes (CSGs) in the NHS laboratories across the UK. Still convening for monthly national meetings, CanVIG-UK develops national consensus guidance and delivers training and education, among other key activities. […]
Frequent FBN2 Variants in Pectus Excavatum Highlight Underlying Phenotypic Variability (Contributed by Dr. Yongjia Yang)
Pectus excavatum (PE) is the most common chest wall deformity, causing a sunken breastbone that can affect breathing and heart function. Most cases occur without a known cause. In our study of 290 children with PE, we discovered that changes in the FBN2 gene—previously linked to a rare syndrome—are surprisingly common among these patients. Using […]
Longest surviving patient with a homozygous splice-altering EGFR pathogenic variant presenting with skin autoinflammation and a Bartter-like salt-losing tubulopathy (Contributed by Dr. Hassan Vahidnezhad)
Bartter syndrome is a rare inherited kidney disease that makes the body lose too much salt. Usually, the cause is a fault in one of seven known genes. None of this was observed in a teenage boy from an inbred family. Instead, his DNA had a change in a different gene, EGFR, which also affected […]