Structural genomic variants

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Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing

Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant AS plays an important role in regulating various diseases, including cancers.

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Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure

Alzheimer’s disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, the specific effects that pathological mutations and coding variants associated with AD have on the cellular composition of the brain are often ignored.

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Complex structural variants in Mendelian disorders: Identification and breakpoint resolution using short- and long-read genome sequencing

Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation.

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Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants

We investigated the features of the genomic rearrangements in a cohort of 50 male individuals with proteolipid protein 1 (PLP1) copy number gain events who were ascertained with Pelizaeus-Merzbacher disease (PMD; MIM: 312080). We then compared our new data to previous structural variant mutagenesis studies involving the Xq22 region of the human genome.

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From cytogenetics to cytogenomics: Wholegenome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability

Since different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test.

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Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants

Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients carrying de novo SVs are frequently unknown.

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Mapping genetic variations to threedimensional protein structures to enhance variant interpretation: a proposed framework

The translation of personal genomics to precision medicine depends on the accurate interpretation of the multitude of genetic variants observed for each individual. However, even when genetic variants are predicted to modify a protein, their functional implications may be unclear.

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Next-generation mapping: A novel approach for detection of pathogenic structural variants with a potential utility in clinical diagnosis

Massively parallel DNA sequencing, such as exome sequencing, has become a routine clinical procedure to identify pathogenic variants responsible for a patient’s phenotype. Exome sequencing has the capability of reliably identifying inherited and de novo single-nucleotide variants, small insertions, and deletions.

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Alternate-locus aware variant calling in whole genome sequencing

The last two human genome assemblies have extended the previous linear golden-path paradigm of the human genome to a graph-like model to better represent regions with a high degree of structural variability. The new model offers opportunities to improve the technical validity of variant calling in whole-genome sequencing (WGS).

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ClinSV: Clinical grade structural and copy number variant detection from whole genome sequencing data

Whole genome sequencing (WGS) has the potential to outperform clinical microarrays for the detection of structural variants (SV) including copy number variants (CNVs), but has been challenged by high false positive rates.

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Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers

Inflammatory breast cancer (IBC) has a highly invasive and metastatic phenotype. However, little is known about its genetic drivers. To address this, we report the largest cohort of whole-genome sequencing (WGS) of IBC cases.

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Optimizing Nanopore sequencing-based detection of structural variants enables individualized circulating tumor DNA-based disease monitoring in cancer patients

Here, we describe a novel approach for rapid discovery of a set of tumor-specific genomic structural variants (SVs), based on a combination of low coverage cancer genome sequencing using Oxford Nanopore with an SV calling and filtering pipeline. We applied the method to tumor samples of high-grade ovarian and prostate cancer patients and validated on average ten somatic SVs per patient with breakpoint-spanning PCR mini-amplicons.

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Haplotype-resolved germline and somatic alterations in renal medullary carcinomas

Renal medullary carcinomas (RMCs) are rare kidney cancers that occur in adolescents and young adults of African ancestry. Although RMC is associated with the sickle cell trait and somatic loss of the tumor suppressor, SMARCB1, the ancestral origins of RMC remain unknown. Further, characterization of structural variants (SVs) involving SMARCB1 in RMC remains limited.

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Artificial intelligence enables comprehensive genome interpretation and nomination of candidate diagnoses for rare genetic diseases

Clinical interpretation of genetic variants in the context of the patient’s phenotype is becoming the largest component of cost and time expenditure for genome-based diagnosis of rare genetic diseases. Artificial intelligence (AI) holds promise to greatly simplify and speed genome interpretation by integrating predictive methods with the growing knowledge of genetic disease.

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Assessing the clinical utility of protein structural analysis in genomic variant classifcation: Experiences from a diagnostic laboratory

The widespread clinical application of genome-wide sequencing has resulted in many new diagnoses for rare genetic conditions, but testing regularly identifies variants of uncertain significance (VUS).

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SvAnna: Efficient and accurate pathogenicity prediction of coding and regulatory structural variants in long-read genome sequencing

Structural variants (SVs) are implicated in the etiology of Mendelian diseases but have been systematically underascertained owing to sequencing technology limitations. Long-read sequencing enables comprehensive detection of SVs, but approaches for prioritization of candidate SVs are needed.

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The multiple de novo copy number variant (MdnCNV) phenomenon presents with peri-zygotic DNA mutational signatures and multilocus pathogenic variation

The multiple de novo copy number variant (MdnCNV) phenotype is described by having four or more constitutional de novo CNVs (dnCNVs) arising independently throughout the human genome within one generation. It is a rare peri-zygotic mutational event, previously reported to be seen once in every 12,000 individuals referred for genome-wide chromosomal microarray analysis due to congenital abnormalities.

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Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers

African ancestry is a significant risk factor for advanced prostate cancer (PCa). Mortality rates in subSaharan Africa are 2.5-fold greater than global averages. However, the region has largely been excluded from the benefits of whole genome interrogation studies. Additionally, while structural variation (SV) is highly prevalent, PCa genomic studies are still biased towards small variant interrogation

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Comprehensive de novo mutation discovery with HiFi long-read sequencing

Long-read sequencing (LRS) techniques have been very successful in identifying structural variants (SVs). However, the high error rate of LRS made the detection of small variants (substitutions and short indels

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High level of complexity and global diversity of the 3q29 locus revealed by optical mapping and long-read sequencing

High sequence identity between segmental duplications (SDs) can facilitate copy number variants (CNVs) via non-allelic homologous recombination (NAHR). These CNVs are one of the fundamental causes of genomic disorders such as the 3q29 deletion syndrome (del3q29S).

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