Genetic Screening of a Nonsyndromic Amelogenesis Imperfecta Patient Cohort Using a Custom smMIP Reagent for Selective Enrichment of Target Loci.

Amelogenesis is the process of tooth enamel formation, and genetic variants disrupting it cause the Mendelian inherited disorder amelogenesis imperfecta (AI). AI patients have weak, discoloured or brittle enamel, caused by reduced enamel quantity or mineralisation. AI can occur in isolation or, less commonly, as part of a syndrome.

Exome sequencing reveals broad genetic heterogeneity for neuromuscular disorders in consanguineous Pakistani Families.

Neuromuscular disorders comprise the majority of neurogenetic conditions, generally characterized by overlapping clinical symptoms, such as spastic paraplegia, muscular abnormalities, and ataxia. In low- and middle-income countries (LMICs), many patients remain undiagnosed or are misdiagnosed. For many NMDs, early diagnosis helps reduce the impact and mortality of the disorder, particularly in LMICs such as Pakistan, and reduces the burden on the healthcare system.

AgileMultiIdeogram: Rapid Identification and Visualization of Autozygous Regions Using Illumina Short-Read Sequencing Data.

Rare autosomal recessive diseases are a major cause of mortality and morbidity. They occur more frequently in individuals with consanguineous parents, in which case the pathogenic variants are often located within regions of genetic identity by descent. A well-established and effective way of identifying these "autozygous" genomic regions has been to search for runs of homozygous genotypes in microarray SNP data.

Early-Onset Movement Disorder Syndrome Caused by Biallelic Variants in PDE1B Encoding Phosphodiesterase 1B.

Background: Breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in basal ganglia cells through hydrolysis of diesteric bonds, primarily by PDE10A and PDE1B, is essential for normal human movement. While biallelic loss-of-function variants in PDE10A are known to cause hyperkinetic movement disorders, the role of PDE1B in human disease has not been characterized.

Objectives: We aimed to define the phenotypic and molecular characteristics of a novel autosomal recessive disorder caused by biallelic PDE1B variants.

Mapping VEXAS-associated and rare UBA1 variants in the United Kingdom: Insights from patient cohorts and the general population.

Somatic mutations in UBA1 are linked to VEXAS syndrome, a late-onset inflammatory disorder with rheumatological and haematological features, primarily affecting elderly men. This study examines the epidemiology of VEXAS in the United Kingdom using genomic databases and patient cohorts to estimate prevalence, identify novel UBA1 variants and predict their pathogenicity. Analysing data from the UK Biobank, 100 000 Genomes Project and clinical diagnostic laboratories, we found that VEXAS prevalence in UK males over 50 is lower than in US-based cohorts.

Treatment outcomes in patients with VEXAS syndrome: a retrospective cohort study.

Background: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently described autoinflammatory disorder with little therapeutic evidence. We compared treatment outcomes of targeted therapies versus prednisolone alone in the largest UK cohort of patients with VEXAS syndrome to date.

Methods: In this retrospective cohort study, we analysed the outcomes of targeted therapies in patients with VEXAS syndrome in six tertiary referral centres across the UK between July 22, 2014, and Oct 19, 2024.

The contradictory role of febuxostat in ABCG2 expression and potentiating hypericin-mediated photodynamic therapy in colorectal cancers.

Photodynamic Therapy (PDT) is an emerging method to treat colorectal cancers (CRC). Hypericin (HYP) is an effective mediator of PDT and the ABCG2 inhibitor, Febuxostat (FBX) could augment PDT. HT29 and HEK293 cells showed light dependant cytotoxic response to PDT in both 2D and 3D cell models.

IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy.

Background: Glioblastoma (GBM) brain tumors lacking IDH1 mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumors almost always fatally recur.

Results: Using RNA sequencing data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumors, we identify two responder subtypes based on longitudinal changes in gene expression.

A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.

Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.

Heterozygous variants are a frequent cause of amelogenesis imperfecta.

Background: Collagen XVII is most typically associated with human disease when biallelic variants (>230) cause junctional epidermolysis bullosa (JEB), a rare, genetically heterogeneous, mucocutaneous blistering disease with amelogenesis imperfecta (AI), a developmental enamel defect. Despite recognition that heterozygous carriers in JEB families can have AI, and that heterozygous variants also cause dominant corneal epithelial recurrent erosion dystrophy (ERED), the importance of heterozygous variants causing dominant non-syndromic AI is not widely recognised.

Methods: Probands from an AI cohort were screened by single molecule molecular inversion probes or targeted hybridisation capture (both a custom panel and whole exome sequencing) for variants.

D-Type Cyclins in Development and Disease.

D-type cyclins encode G1/S cell cycle checkpoint proteins, which play a crucial role in defining cell cycle exit and progression. Precise control of cell cycle exit is vital during embryonic development, with defects in the pathways regulating intracellular D-type cyclins resulting in abnormal initiation of stem cell differentiation in a variety of different organ systems. Furthermore, stabilisation of D-type cyclins is observed in a wide range of disorders characterized by cellular over-proliferation, including cancers and overgrowth disorders.

De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood.

Purpose: Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene.

Targeted nanopore sequencing enables complete characterisation of structural deletions initially identified using exon-based short-read sequencing strategies.

Background: The widespread adoption of exome sequencing has greatly increased the rate of genetic diagnosis for inherited conditions. However, the detection and validation of large deletions remains challenging. While numerous bioinformatics approaches have been developed to detect deletions from whole - exome sequencing and targeted panels, further work is typically required to define the physical breakpoints or integration sites.

Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis.

Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability.

Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.

Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors.

Missense mutation of MAL causes a rare leukodystrophy similar to Pelizaeus-Merzbacher disease.

Leukodystrophies are a heterogenous group of genetic disorders, characterised by abnormal development of cerebral white matter. Pelizaeus-Merzbacher disease is caused by mutations in PLP1, encoding major myelin-resident protein required for myelin sheath assembly. We report a missense variant p.

MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer.

Background: poor prognosis primary breast cancers are typically treated with cytotoxic chemotherapy. However, recurrences remain relatively common even after this aggressive therapy. Comparison of matched tumours pre- and post-chemotherapy can allow identification of molecular characteristics of therapy resistance and thereby potentially aid discovery of novel predictive markers or targets for chemosensitisation.

Genetics of somatic auto-inflammatory disorders.

Systemic autoinflammatory disorders (SAIDs) encompass a heterogeneous group of monogenic disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Genetic studies have facilitated the identification of Mendelian forms of SAIDs but many patients still remain without a diagnosis. Recent studies have uncovered that somatic (acquired) mutations can cause later-onset SAIDs.

Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project.

Background: Primary ciliopathies represent a group of inherited disorders due to defects in the primary cilium, the 'cell's antenna'. The 100,000 Genomes Project was launched in 2012 by Genomics England (GEL), recruiting National Health Service (NHS) patients with eligible rare diseases and cancer. Sequence data were linked to Human Phenotype Ontology (HPO) terms entered by recruiting clinicians.

An Atypical Autoinflammatory Disease Due to an LRR Domain NLRP3 Mutation Enhancing Binding to NEK7.

The NLRP3 inflammasome is a vital mediator of innate immune responses. There are numerous NLRP3 mutations that cause NLRP3-associated autoinflammatory diseases (NLRP3-AIDs), mostly in or around the NACHT domain. Here, we present a patient with a rare leucine-rich repeat (LRR) domain mutation, p.