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PubMed2026

Integrating Optical Genome Mapping into the Genetic Diagnostic Algorithm: Clinical Utility in Unresolved Autosomal Recessive Disorders from a Large Cohort.

INTRODUCTION: The identification of precise genetic etiologies is indispensable for the clinical management of monogenic disorders. However, conventional diagnostic methods and exome sequencing (ES) frequently fail to identify complex structural variations (SVs), leaving the genetic basis unexplained in approximately 30-60% of suspected cases. Optical genome mapping (OGM) emerges as a high-resolution technology capable of detecting cryptic SVs inaccessible to standard methodologies. METHODS: In this study, we evaluated the clinical utility of integrating OGM into the diagnostic algorithm for unresolved monogenic diseases. Following negative or inconclusive results from standard ES pipelines, OGM was applied to a targeted subset of patients (n = 7) selected from a comprehensive clinical cohort of 1,257 individuals with suspected genetic disorders. RESULTS: The integration of OGM identified candidate SVs that may represent the second allelic alteration in two distinct cases; however, confirmation through parental segregation analysis remains pending. Specifically, OGM identified an intronic insertion in the TTLL5 gene and a deletion in a putative regulatory region approximately 400 kb upstream of the NMNAT1 gene, both of which were missed by prior diagnostic testing. CONCLUSION: Our findings suggest that OGM has potential value in investigating the missing heritability of autosomal recessive disorders. By detecting candidate SVs invisible to conventional methods, OGM may warrant consideration as a complementary diagnostic approach following inconclusive ES; however, larger cohorts and confirmatory functional studies are needed to establish its clinical utility.

Autosomal recessive disorders↗
PubMed2002

Analyzing array data using supervised methods.

Pharmacogenomics is the application of genomic technologies to drug discovery and development, as well as for the elucidation of the mechanisms of drug action on cells and organisms. DNA microarrays measure genome-wide gene expression patterns and are an important tool for pharmacogenomic applications, such as the identification of molecular targets for drugs, toxicological studies and molecular diagnostics. Genome-wide investigations generate vast amounts of data and there is a need for computational methods to manage and analyze this information. Recently, several supervised methods, in which other information is utilized together with gene expression data, have been used to characterize genes and samples. The choice of analysis methods will influence the results and their interpretation, therefore it is important to be familiar with each method, its scope and limitations. Here, methods with special reference to applications for pharmacogenomics are reviewed.

Artificial Intelligence↗
PubMed2006

Genomic platforms for cancer research: potential diagnostic and prognostic applications in clinical oncology.

The completion of the Human Genome Project and the achievement of similar goals in other organisms have generated a huge amount of free available information with high potential in biomedical sciences. However, the identification of the DNA sequence was only a starting point for genomic research. This research has been facilitated by the development of new powerful genomic tools that allow the use of the wide amount of genomic information generated to address new biological and biomedical questions. One of these widely accepted and accessible technologies is DNA microarrays. Although the most popular use of DNA microarrays is gene expression profiling, due to the continuous advances in microarray technologies, scientists have also successfully used them for multiple applications, including genotyping, re-sequencing, DNA copy number analysis and DNA methylation. In short, DNA microarrays are changing the way cancer research scientists are addressing different biological questions and will allow the translation of genome research to clinical practice.

Biomedical Research↗
PubMed2025

Whole-genome sequencing, as a powerful diagnostic tool in hearing loss, reveals novel variants in PTPRQ missed by whole-exome sequencing.

BACKGROUND/OBJECTIVES: Hearing loss (HL) is one of the most common congenital disorders, affecting 1-2 in 1,000 newborns. Modern genetic diagnostics using large gene panels and/or whole exome analysis (WES) can identify disease-causing mutations in 25-50 % of patients, with higher solve rates in individuals with earlier onset. RESULTS: Here, we used whole-genome sequencing (WGS) to reanalyze 14 index patients/families who remained without genetic diagnosis by WES. We were able to identify the genetic cause of HL in 6 families (43 %). Two families were diagnosed with DFNB84A caused by compound heterozygous recessive mutations in PTPRQ. Three of the four underlying variants, including a structural variant, a deep intronic variant, and a splice variant, escaped detection by WES. Minigene assays confirmed the pathogenicity of the intronic and the splice variants. In addition, we used protein 3D structure prediction and rigid ligand docking to study the pathogenicity of variants that escape nonsense-mediated decay. CONCLUSION: In our study, we present four novel variants in PTPRQ, three of which were detected only by WGS. To our knowledge, we report here the first pathogenic deep intronic PTPRQ variant causing HL. Our results suggest that the mutational spectrum of PTPRQ is not well covered by standard WES and that PTPRQ-associated hearing loss may be more frequent than previously thought. WGS provides an additional layer of information in the diagnostics of HL.

Humans↗
PubMed2025

A universal, high-quality, and high-yield DNA purification method for mycobacteria, including Mycobacterium tuberculosis: large-scale assessment of the chloroform-bead method.

UNLABELLED: Genomic analysis of mycobacteria has become increasingly crucial for understanding drug-resistance mechanisms, molecular epidemiology, and pathogenesis. However, efficient extraction of high-molecular-weight genomic DNA from these organisms remains challenging because of their thick mycolic acid-rich cell walls. In this study, we report the chloroform-bead method, a universal DNA extraction protocol that combines chemical and mechanical disruptions to overcome these challenges. Multi-laboratory evaluation (16 sites) demonstrated the chloroform-bead method's superiority over conventional methods for Mycobacterium tuberculosis (DNA yield: 17.9 vs 1.9 &#xb5;g, purity A260/A230: 1.86 vs 1.22, both P < 0.001). Single-facility assessment extended these findings to >32 nontuberculous mycobacterial species (n = 1,058), showing performance comparable to M. tuberculosis (n = 1,000), with both achieving median yields of 22.2 &#xb5;g DNA and consistent quality metrics. The chloroform-bead method significantly reduced the processing time from 2 to 3 days to 2 h while ensuring complete sample sterilization, eliminating the need for species-specific optimization. This streamlined and universally applicable protocol represents a practical advancement in mycobacterial DNA extraction methodology, ideal for high-throughput genomic studies and routine clinical diagnostics. IMPORTANCE: Mycobacterial genomics is crucial for understanding pathogenesis and drug resistance; however, DNA extraction remains a significant challenge because of its unique cell wall. Traditional methods rely on enzymatic treatments, resulting in complex and time-consuming protocols with variable results. The chloroform-bead method introduces a paradigm shift by chemically and mechanically disrupting the mycolic acid layer and eliminating the need for enzymatic treatment. This standardized approach ensures consistent, high-quality DNA extraction across diverse mycobacterial species, thereby enhancing research capabilities and clinical applications.

Chloroform↗
PubMed2026

Genomic profiling as an option for ovarian cancer diagnostics.

INTRODUCTION: Ovarian cancer (OC) is a highly heterogeneous and lethal gynecological malignancy. Precision oncology has shifted the management paradigm to comprehensive molecular profiling. Genomic-based diagnostics are now a clinical necessity for accurate prognostic stratification and the rational selection of targeted therapeutics, such as PARP and immune checkpoint inhibitors. AREAS COVERED: This review evaluates current literature regarding the distinct genomic landscapes defining OC histotypes to underlined the role of molecular profiling in the diagnostic field of OC. We discuss the practical implementation, technical aspect, and clinical validity of the main molecular diagnostic platforms, focusing on tissue-based Comprehensive Genomic Profiling (CGP) and Homologous Recombination Deficiency (HRD). Furthermore, we explore emerging translational data on liquid biopsy (LBx) applications. EXPERT OPINION: While current tissue-based methodologies provide critical baseline data, the OC diagnostic paradigm must pivot from static testing to proactive and longitudinal tracking. Integrating advanced LBx approaches enables a real-time monitoring of dynamic parameters as minimal residual disease (MRD) and acquired resistance. Integrating these dynamic blood-based assays with multi-omic profiling and artificial intelligence (AI)-driven tools allows a full understanding of the complex tumor behavior.

Humans↗
PubMed2025

Genome-wide association studies of binge eating behaviour and anorexia nervosa yield insights into the unique and shared biology of eating disorder phenotypes.

Eating disorders -including anorexia nervosa (AN), bulimia nervosa, and binge eating disorder-are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. We conducted the first genomic meta-analysis of binge eating behaviour (BE; 39,279 cases, 1,227,436 controls), alongside new analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six loci associated with BE, including loci associated with higher body mass index (BMI) and impulse-control behaviours. AN GWAS yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry cohorts. BE and AN exhibited similar positive genetic correlations with psychiatric disorders, but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with BMI. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries.

Journal Article↗
PubMed2026

Genomic meta-analyses of binge-eating behavior and anorexia nervosa yield insights into the unique and shared biology of eating disorder phenotypes.

Eating disorders-including anorexia nervosa (AN), bulimia nervosa and binge-eating disorder-are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. Here we conducted a genomic meta-analysis of case-control studies of binge-eating behavior (BE; 39,279 cases, 1,227,436 controls), alongside analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six BE-associated loci, including loci associated with a higher body mass index and impulse-control behaviors. AN genome-wide association studies yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry studies. BE and AN exhibited similar positive genetic correlations with psychiatric disorders but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with body mass index. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries.

Behavioural genetics↗
PubMed1994

Nested PCR optimized for detection of Bordetella pertussis in clinical nasopharyngeal samples.

Several genes and sequences in Bordetella pertussis have been used as targets in diagnostic PCR assays. A previously developed single-step PCR assay for the detection of B. pertussis was based on an insertion sequence, IS480, that is present in about 70 to 80 copies in each genome. The diagnostic sensitivity, specificity, and reliability of this assay with aspirated and heat-treated samples from the nasopharynx of patients and their contacts was improved by the use of a nested PCR configuration. The nested PCR assay produced a 205-bp fragment with all of the 115 B. pertussis strains tested and was negative with all strains belonging to other Bordetella species (n = 44) as well as other bacteria commonly found in the upper respiratory tract (n = 115). The diagnostic value of the assay was verified by giving positive results for B. pertussis in all the 51 nasopharyngeal aspirates from culture-positive patients. The assay also detected 18 positive aspirates from a total of 196 culture-negative patients. A confirmatory cleavage of the 205-bp nested PCR product by MvaI gave in all cases two bands of 88 and 117 bp. In conclusion, this newly developed nested PCR assay was shown to be reasonably fast and uncomplicated, with an optimal sensitivity and a high degree of specificity for the diagnosis of B. pertussis in aspirated nasopharyngeal samples processed simply by heat treatment. The detection level in the nested PCR was about 10 bacteria per ml, or seven to eight insertion sequence copies per 10 microliters of boiled sample.

Base Sequence↗
PubMed2001

Tissue microarray technology for high-throughput molecular profiling of cancer.

Tissue microarray (TMA) technology allows rapid visualization of molecular targets in thousands of tissue specimens at a time, either at the DNA, RNA or protein level. The technique facilitates rapid translation of molecular discoveries to clinical applications. By revealing the cellular localization, prevalence and clinical significance of candidate genes, TMAs are ideally suitable for genomics-based diagnostic and drug target discovery. TMAs have a number of advantages compared with conventional techniques. The speed of molecular analyses is increased by more than 100-fold, precious tissues are not destroyed and a very large number of molecular targets can be analyzed from consecutive TMA sections. The ability to study archival tissue specimens is an important advantage as such specimens are usually not applicable in other high-throughput genomic and proteomic surveys. Construction and analysis of TMAs can be automated, increasing the throughput even further. Most of the applications of the TMA technology have come from the field of cancer research. Examples include analysis of the frequency of molecular alterations in large tumor materials, exploration of tumor progression, identification of predictive or prognostic factors and validation of newly discovered genes as diagnostic and therapeutic targets.

Animals↗
PubMed1997

Development of mycobacterial species-specific DNA probes by subtraction hybridization.

Subtraction hybridization was used to identify sequences of Mycobacterium bovis DNA which might be of diagnostic value. Genomic DNA from Mycobacterium avium, isolated commonly from cattle and whose tuberculin is used in the comparative intradermal tuberculin test, was subtracted from M. bovis genomic DNA. A novel sequence, of 131 bp, which appears to be Mycobacterium tuberculosis complex-specific was identified. The specificity of this sequence was stringently tested by a probe and polymerase chain reaction (PCR) assay. Nucleotide identity determination and sequence comparisons revealed that the 131-bp sequence is located directly upstream of a potential isocitrate dehydrogenase (IDH) coding gene and may be of diagnostic value, enabling differentiation of M. tuberculosis complex mycobacteria from other mycobacterial species.

Animals↗
PubMed2005

Genomic and bioinformatics analyses of HAdV-4vac and HAdV-7vac, two human adenovirus (HAdV) strains that constituted original prophylaxis against HAdV-related acute respiratory disease, a reemerging epidemic disease.

Vaccine strains of human adenovirus serotypes 4 and 7 (HAdV-4vac and HAdV-7vac) have been used successfully to prevent adenovirus-related acute respiratory disease outbreaks. The genomes of these two vaccine strains have been sequenced, annotated, and compared with their prototype equivalents with the goals of understanding their genomes for molecular diagnostics applications, vaccine redevelopment, and HAdV pathoepidemiology. These reference genomes are archived in GenBank as HAdV-4vac (35,994 bp; AY594254) and HAdV-7vac (35,240 bp; AY594256). Bioinformatics and comparative whole-genome analyses with their recently reported and archived prototype genomes reveal six mismatches and four insertions-deletions (indels) between the HAdV-4 prototype and vaccine strains, in contrast to the 611 mismatches and 130 indels between the HAdV-7 prototype and vaccine strains. Annotation reveals that the HAdV-4vac and HAdV-7vac genomes contain 51 and 50 coding units, respectively. Neither vaccine strain appears to be attenuated for virulence based on bioinformatics analyses. There is evidence of genome recombination, as the inverted terminal repeat of HAdV-4vac is initially identical to that of species C whereas the prototype is identical to species B1. These vaccine reference sequences yield unique genome signatures for molecular diagnostics. As a molecular forensics application, these references identify the circulating and problematic 1950s era field strains as the original HAdV-4 prototype and the Greider prototype, from which the vaccines are derived. Thus, they are useful for genomic comparisons to current epidemic and reemerging field strains, as well as leading to an understanding of pathoepidemiology among the human adenoviruses.

Acute Disease↗
PubMed2005

Genomic and transcription studies as diagnostic tools for a prenatal detection of X-linked dilated cardiomyopathy due to a dystrophin gene mutation.

X-linked dilated cardiomyopathy (XLDC) represents a form of dystrophinopathy with exclusive heart involvement. Here a prenatal diagnosis of this condition performed in a family with XLDC is described. In this family, the causative mutation was a pure intronic deletion, which induces the splicing of a novel, aberrant, and out-of-frame exon into the dystrophin transcript. The genetic test was performed by defining both the DNA (villous) and the RNA (amniocyte) configuration. The prenatal diagnosis determined that the fetus was female, and a carrier of the genomic deletion. RNA analysis on cultured amniocytes revealed the presence of an easily detectable dystrophin transcript, as well as the co-existence of both the wild-type and the abnormal splicing profile. Our analysis represents the first report of a prenatal diagnosis in XLDC and also indicates the feasibility of dystrophin mutation detection on RNA from amniocytes. This finding suggests that the dystrophin splicing pattern in amniocytes and skeletal muscle is similar, and that, therefore, this approach could be used in other prenatal dystrophin mutation detection, where abnormal RNA splicing is thought to play a role, or for specific cases in which no mutations have been identified in the coding regions.

Cardiomyopathy, Dilated↗
PubMed2026

Mapping the development pipeline of genomic point-of-care tests: a horizon scan.

INTRODUCTION: As precision medicine increasingly relies on genetic information, the development of reliable genomic point-of-care tests (POCTs) is essential. However, the number of technologies that have reached true clinical usability is limited. There is a growing need for POCTs that enable rapid, accurate analysis of human genetic variation, particularly across diverse clinical settings without requiring specialist expertise. AREAS COVERED: This horizon scan aimed to provide an overview of the development pipeline of POCTs to identify variation(s) in the genome and epigenome that enable the use of genetic information to inform diagnosis, prognosis, and treatment decisions in any clinical area. Database (Embase and MEDLINE) and clinical trial registry (ClinicalTrials.gov) searches were conducted from 2019 to 19 December 2024; 346 unique technologies were identified. EXPERT OPINION AND COMMENTARY: A range of purposes and conditions were identified; the most common being diagnosis (n&#x2009;=&#x2009;263) and cancer (n&#x2009;=&#x2009;237) respectively. We defined 'true POCTs' as those that were highly automated, capable of analyzing complex samples, and operable by non-specialists. Only 36&#x2009;met these criteria; six are already on the market, one is in clinical trials, and the remaining 29 are at various stages of development. Overall, most technologies were in early stages of development, highlighting the need for further innovation and validation.

Point-of-care↗
PubMed2003

Molecular characterization of acute leukemias by use of microarray technology.

Accurate subclassification of leukemia and the identification of prognostic determinants are essential to guide therapy and to improve patients' outcome. According to present standards, pre-therapeutic assessment depends on a combination of different methods. We aimed to expand the molecular characterization of different acute leukemia subtypes to identify new genome-wide diagnostic markers. Total RNA from 90 adult patients suffering from acute lymphoblastic leukemia (ALL, n = 25) and acute myeloid leukemia (AML, n = 65) was extracted at diagnosis and high density oligonucleotide microarrays were used to analyze the expression profiles of 12,000/22,000 genes in all specimens (Affymetrix U95Av2/U133A). All cases were thoroughly characterized by individual combinations of cytomorphology, cytogenetics, multiparameter immunophenotyping, and molecular genetics. The expression signature of a small set of differentially expressed genes was sufficient to accurately discriminate eight clinically relevant acute leukemia subgroups. Underlying chromosomal aberrations or immunophenotypical characteristics were strictly correlated with a distinct gene expression pattern for AML with t(8;21), t(15;17), t(11q23)/MLL, or inv(16) as well as for precursor B-ALL with t(9;22), t(8;14), or t(11q23)/MLL and precursor T-ALL. These data support a possible future application of microarray technology for classification of the acute leukemias.

Acute Disease↗
PubMed2006

Polyomaviruses and human diseases.

Polyomaviruses are small, nonenveloped DNA viruses, which are widespread in nature. In immunocompetent hosts, the viruses remain latent after primary infection. With few exceptions, illnesses associated with these viruses occur in times of immune compromise, especially in conditions that bring about T cell deficiency. The human polyomaviruses BKV and JCV are known to cause, respectively, hemorrhagic cystitis in recipients of bone marrow transplantation and progressive multifocal leukoencephalopathy in immunocompromised patients, for example, by HIV infection. Recently, transplant nephropathy due to BKV infection has been increasingly recognized as the cause for renal allograft failure. Quantitation of polyomavirus DNA in the blood, cerebrospinal fluid, and urine, identification of virus laden "decoy cells" in urine, and histopathologic demonstration of viral inclusions in the brain parenchyma and renal tubules are the applicable diagnostic methods. Genomic sequences of polyomaviruses have been reported to be associated with various neoplastic disorders and autoimmune conditions. While various antiviral agents have been tried to treat polyomavirus-related illnesses, current management aims at the modification and/or improvement in the hosts' immune status. In this chapter, we provide an overview of polyomaviruses and briefly introduce its association with human diseases, which will be covered extensively in other chapters by experts in the field.

Antiviral Agents↗
PubMed2006

Strategies to identify potential therapeutic target sites in RNA.

Antisense agents are powerful tools to inhibit gene expression in a sequence-specific manner. They are used for functional genomics, as diagnostic tools and for therapeutic purposes. Three classes of antisense agents can be distinguished by their mode of action: single-stranded antisense oligodeoxynucleotides; catalytic active RNA/DNA such as ribozymes, DNA- or locked nucleic acid (LNA)zymes; and small interfering RNA molecules known as siRNA. The selection of target sites in highly structured RNA molecules is crucial for their successful application. This is a difficult task, since RNA is assembled into nucleoprotein complexes and forms stable secondary structures in vivo, rendering most of the molecule inaccessible to intermolecular base pairing with complementary nucleic acids. In this review, we discuss several selection strategies to identify potential target sites in RNA molecules. In particular, we focus on combinatorial library approaches that allow high throughput screening of sequences for the design of antisense agents.

Animals↗