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BackgroundTo assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry.MethodsWe sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3634), compared findings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional studies.ResultsSingaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (pathogenic/likely pathogenic: 18%, P

Identification of ancestry‐specific pathogenic variants is imperative for diagnostic, treatment, management and prevention strategies, and to understand penetrance/modifiers on risk. Our study aimed to determine the clinical significance of a recurrent BRCA1 c.442‐22_442‐13del variant of unknown significance identified among 13 carriers from six Chinese families, all with a significant history of breast and/or ovarian cancer. We further aimed to establish whether this was due to a founder effect and explore its origins. Haplotype analysis, using nine microsatellite markers encompassing 2.5 megabase pairs around the BRCA1 locus, identified a common haploblock specific to the variant carriers, confirming a founder effect. Variant age was estimated to date back 77.9 generations to 69 bc using the Gamma approach. On principal component analysis using single nucleotide polymorphisms merged with 1000 Genomes dataset, variant carriers were observed to overlap predominantly with the southern Han Chinese population. To determine pathogenicity of the variant, we assessed the functional effect on RAD51 foci formation as well as replication fork stability upon induction of DNA damage and observed an impaired DNA repair response associated with the variant. In summary, we identified an ancient Chinese founder mutation dating back 77.9 generations, possibly common among individuals of southern Han Chinese descent. Using evidence from phenotypic/family history studies, segregation analysis and functional characterization, the BRCA1 variant was reclassified from uncertain significance to pathogenic. What's new? Extensive databases of BRCA1/2 variants have helped researchers develop diagnostic and treatment strategies for breast cancer. However, most of this information has been obtained from populations of European descent. In the present study, the authors were able to identify an ancient founder mutation in BRCA1 that is pathogenic and may be common among individuals of Han Chinese descent. In addition to its importance for appropriate patient care, this approach to studying ancestry‐specific variants may also aid in developing techniques to detect pathogenic mutations that might otherwise be missed. [ABSTRACT FROM AUTHOR]

We screened 662 subjects comprising 462 essential tremor (ET) subjects (285 sporadic, 125 with family history, and 52 probands from well-characterized ET pedigrees) and 200 controls and identified pathogenic NOTCH2NLC GGC repeat expansions in 4 sporadic ET patients. Two patients were followed up for >1 decade; one with 90 repeats remained an ET phenotype that did not evolve after 40 years, whereas another patient with 107 repeats developed motor symptoms and cognitive impairment after 8 to 10 years. Neuroimaging in this patient revealed severe leukoencephalopathy; diffusion-weighted imaging hyperintensity in the corticomedullary junction and skin biopsy revealed intranuclear inclusions suggestive of intranuclear inclusion body disease (NIID). No GGC repeats of >60 units were detected in familial ET cases and controls, although 4 ET patients carried 47 to 53 "intermediate" repeats. NOTCH2NLC GGC repeat expansions can be associated with sporadic ET. Carriers presenting with a pure ET phenotype may or may not convert to NIID up to 4 decades after initial tremor onset. ANN NEUROL 2020;88:614-618. [ABSTRACT FROM AUTHOR]

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder associated with GGC repeats of >60 to 500 copies in the 5′‐untranslated region of NOTCH2NLC. The clinical and genetic characterization of NIID outside of East Asia remains unknown. We identified twelve patients who underwent genetic testing using long‐read sequencing or repeat primed polymerase chain reaction. All were positive for a GGC repeat expansion; the median repeat length was 107 (range 92‐138). Ten were Chinese and two of Malay ethnicity. Age at onset ranged from 50 to 69 years. Eight (66.7%) patients had dementia, while four (33.3%) patients were oligosymptomatic, without typical NIID symptoms of dementia, Parkinsonism, or muscle weakness. GGA interruptions within the GGC expansion were present in four patients; the number of GGA interruptions was highest (6.71%) in the patient with the earliest age at onset (50 years). Median plasma neurofilament light level was 47.3 pg/mL in seven patients (range 26‐380 pg/mL). The highest level (380 pg/mL) was found in one patient who experienced an encephalitic episode. Overall, we describe a cohort of genetically confirmed NIID patients from Southeast Asia and provide further information that the presence of GGA interruptions within GGC repeat expansions may serve as a potential genetic modifier in NIID. [ABSTRACT FROM AUTHOR]

Introduction: Neurodevelopmental disorders (NDDs) comprise conditions that emerge during the child's development and contribute significantly to global health and economic burdens. De-novo variants in CNOT3 have been linked to NDDs and understanding the genotype-phenotype relationship between CNOT3 and NDDs will aid in improving diagnosis and management., Methods: In this study, we report a case of a patient with CNOT3-related NDD who presented with progressive aortic dilatation, a feature not reported previously., Results: Our patient presented with intellectual disorder, dysmorphic facial features, and cardiac anomalies, notably progressive aortic dilatation - a novel finding in CNOT3-related NDD. Genetic testing identified a de-novo 6.3 kbp intragenic deletion in CNOT3, providing a possible genetic basis for her condition., Conclusion: This study presents the first case of CNOT3-related NDD in Southeast Asia, expanding the phenotype to include progressive aortic dilatation and suggesting merit in cardiac surveillance of patients with CNOT3-related NDD. It also emphasizes the importance of genetic testing in diagnosing complex NDD cases as well as reanalysis of 'negative' cases using advanced sequencing technologies to uncover potential hidden genetic etiologies in undiagnosed NDDs., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Field cancerization is suggested to arise from imbalanced differentiation in individual basal progenitor cells leading to clonal expansion of mutant cells that eventually replace the epithelium, although without evidence., Methods: We performed deep sequencing analyses to characterize the genomic and transcriptomic landscapes of field change in two patients with synchronous aerodigestive tract tumors., Results: Our data support the emergence of numerous genetic alterations in cancer-associated genes but refutes the hypothesis that founder mutation(s) underpin this phenomenon. Mutational signature analysis identified defective homologous recombination as a common underlying mutational process unique to synchronous tumors., Discussion: Our analyses suggest a common etiologic factor defined by mutational signatures and/or transcriptomic convergence, which could provide a therapeutic opportunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tan, Shannon, Lim, Teo, Yap, Lek, Tan, Tan, Hendrikson, Liu, Ng, Chong, Guo, Koh, Ng, Rajasegaran, Wong, Seo, Ong, Lim, Teh, Kon, Chia, Soo, Iyer and Ong.)

Objective: Genomic structural variations (SVs) causing rewiring of cis -regulatory elements remain largely unexplored in gastric cancer (GC). To identify SVs affecting enhancer elements in GC ( enhancer-based SVs ), we integrated epigenomic enhancer profiles revealed by paired-end H3K27ac ChIP-sequencing from primary GCs with tumour whole-genome sequencing (WGS) data (PeNChIP-seq/WGS)., Design: We applied PeNChIP-seq to 11 primary GCs and matched normal tissues combined with WGS profiles of >200 GCs. Epigenome profiles were analysed alongside matched RNA-seq data to identify tumour-associated enhancer-based SVs with altered cancer transcription. Functional validation of candidate enhancer-based SVs was performed using CRISPR/Cas9 genome editing, chromosome conformation capture assays (4C-seq, Capture-C) and Hi-C analysis of primary GCs., Results: PeNChIP-seq/WGS revealed ~150 enhancer-based SVs in GC. The majority (63%) of SVs linked to target gene deregulation were associated with increased tumour expression. Enhancer-based SVs targeting CCNE1 , a key driver of therapy resistance, occurred in 8% of patients frequently juxtaposing diverse distal enhancers to CCNE1 proximal regions. CCNE1 -rearranged GCs were associated with high CCNE1 expression, disrupted CCNE1 topologically associating domain (TAD) boundaries, and novel TAD interactions in CCNE1 -rearranged primary tumours. We also observed IGF2 enhancer-based SVs, previously noted in colorectal cancer, highlighting a common non-coding genetic driver alteration in gastric and colorectal malignancies., Conclusion: Integrated paired-end NanoChIP-seq and WGS of gastric tumours reveals tumour-associated regulatory SV in regions associated with both simple and complex genomic rearrangements. Genomic rearrangements may thus exploit enhancer-hijacking as a common mechanism to drive oncogene expression in GC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)