Background: With the advent of next-generation sequencing in genetic testing, predicting the pathogenicity of missense variants represents a major challenge potentially leading to misdiagnoses in the clinical setting. In neurofibromatosis type 1 (NF1...
Background: Practices in somatic variant interpretation and classification vary between Canadian clinical molecular diagnostic laboratories, and understanding of current practices and perspectives is limited. To define gaps and future directions, inc...
High throughput sequencing (HTS) is increasingly important in determining cancer diagnoses, with subsequent prognostic and therapeutic implications. The biology of cancer is becoming increasingly deciphered and it is clear that therapy needs to be in...
Variant interpretation is challenging as it involves combining different levels of evidence in order to evaluate the role of a specific variant in the context of a patient’s disease. Many in-depth refinements followed the original 2015 American...
Objectives: This study aims to demonstrate the role of case-level American College of Medical Genetics (ACMG) criteria, such as familial segregation and pathology data, in providing conclusive evidence for the pathogenicity of ultrarare GLA variants...
The identification of the genetic causes of inherited disorders from next-generation sequencing (NGS) data remains a complicated process, in particular due to challenges in interpretation of the vast amount of generated data and hundreds of candidate...
Pathogenicity predictors are computational tools that classify genetic variants as benign or pathogenic; this is currently a major challenge in genomic medicine. With more than fifty such predictors available, selecting the most suitable tool for cli...
Given the increase in genomic testing in routine clinical use, there is a growing need for digital technology solutions to assist pathologists, oncologists, and researchers in translating variant calls into actionable knowledge to personalize patient...
Large-scale next-generation sequencing (NGS) germline testing is technically feasible today, but variant interpretation represents a major bottleneck in analysis workflows. This includes extensive variant prioritization, annotation, and time-consumin...
In the current marketplace, there are now more than a dozen commercial companies providing pharmacogenetic tests. Each company varies in the panel of genes they test and the variants they are able to screen for. The reports generated by these compani...
In this paper, we study a syntactic construction that has received little attention in the study of Spanish grammar (La masa de pizza congela perfectamente, ‘Pizza dough freezes perfectly’). It is characterized by the presence of a verb i...
The increasing availability of next generation sequencing (NGS) for personal genomics could promote pharmacogenomics (PGx) discovery and application. However, current tools for analysis and interpretation of pharmacogenomic variants from NGS data are...
Background/Objectives: Interpreting missense variants in intrinsically disordered proteins (IDPs) remains a major challenge, as these proteins lack stable structure and are under-represented in experimental and clinical annotations. Variants occurrin...
Implementation of next-generation sequencing (NGS) for the genetic analysis of hereditary diseases has resulted in a vast number of genetic variants identified daily, leading to inadequate variant interpretation and, consequently, a lack of useful cl...
BRCA1/2 variants are prognostic biomarkers for hereditary breast and/or ovarian cancer (HBOC) syndrome and predictive biomarkers for PARP inhibition. In this study, we benchmarked the classification of BRCA1/2 variants from patients with HBOC-related...
Synonymous variants, traditionally regarded as silent mutations due to their lack of impact on protein sequence, structure and function, have been the subject of increasing scrutiny. This commentary explores the emerging evidence challenging the noti...
Accurate prediction of the impact of genetic variants on human health is of paramount importance to clinical genetics and precision medicine. Recent machine learning (ML) studies have tried to predict variant pathogenicity with different levels of su...
Background: Germline genetic variants impacting splicing are a frequent cause of disease. The clinical interpretation of such variants is challenging for many reasons including the immense complexity of splicing mechanisms. While recent advances in s...
Genetic variation in ATP Binding Cassette Subfamily C Member 6 (ABCC6) can cause both pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI). There are 930 distinct missense variants in ABCC6 reported, 87% of which ar...
Background: The accurate interpretation of the BRCA1/2 variant is critical for diagnosing and treating hereditary breast and ovarian cancers. ClinVar is a widely used public database for genetic variants. Conflicting classifications of pathogenicity...
Background/objectives: Obtaining a genetic diagnosis for patients with inherited retinal diseases has become even more important since gene-specific therapies have become available. When genetic screening reveals variants of uncertain significance (V...
Since the start of X-linked adrenoleukodystrophy (ALD) newborn screening in California, more than half of the diagnosed cases were found to have an ATP binding cassette subfamily D member 1 (ABCD1) gene variant of uncertain significance (VUS). To det...
Background/Objectives: Inherited arrhythmogenic syndromes comprise a heterogenic group of genetic entities that lead to malignant arrhythmias and sudden cardiac death. Genetic testing has become crucial to understand the disease etiology and allow fo...
Hereditary breast and/or ovarian cancer is a highly heterogeneous disease with more than 10 known disease-associated genes. In the framework of the BRIDGES project (Breast Cancer Risk after Diagnostic Gene Sequencing), the RAD51C gene has been sequen...
The identification of pathogenic variants in monogenic diseases has been of interest to researchers and clinicians for several decades. However, for inherited diseases with extremely high genetic heterogeneity, such as hearing loss and retinal dystro...
This paper presents the findings of an exploratory study on the continuously generating Big Data on Twitter related to the sharing of information, news, views, opinions, ideas, knowledge, feedback, and experiences about the COVID-19 pandemic, with a...
Germline TP53 variants represent a main genetic cause of breast cancers before 31 years of age. Development of cancer multi-gene panels has resulted in an exponential increase of germline TP53 testing in breast cancer patients. Interpretation of TP53...
Using deep sequencing technologies such as Illumina’s platform, it is possible to obtain reads from the viral RNA population revealing the viral genome diversity within a single host. A range of software tools and pipelines can transform raw de...
The MRE11, RAD50, and NBN genes encode for the nuclear MRN protein complex, which senses the DNA double strand breaks and initiates the DNA repair. The MRN complex also participates in the activation of ATM kinase, which coordinates DNA repair with t...
Gains and losses of large segments of genomic DNA, known as copy number variants (CNVs) gained considerable interest in clinical diagnostics lately, as particular forms may lead to inherited genetic diseases. In recent decades, researchers developed...
The advent of Whole Genome Sequencing (WGS) broadened the genetic variation detection range, revealing the presence of variants even in non-coding regions of the genome, which would have been missed using targeted approaches. One of the most challeng...
Inherited retinal dystrophies are an assorted group of rare diseases that collectively account for the major cause of visual impairment of genetic origin worldwide. Besides clinically, these vision loss disorders present a high genetic and allelic he...
Clinical genomics sequencing is rapidly expanding the number of variants that need to be functionally elucidated. Interpreting genetic variants (i.e., mutations) usually begins by identifying how they affect protein-coding sequences. Still, the three...
The rapid evolution of Next Generation Sequencing in clinical settings, and the resulting challenge of variant reinterpretation given the constantly updated information, require robust data management systems and organized approaches. In this paper,...
This study described TTN gene variants in Ecuadorian patients with hereditary cardiac diseases, integrating genetic ancestry to improve variant interpretation in an underrepresented population. Sixty patients with confirmed hereditary cardiac conditi...
Precision medicine starts with a precision diagnosis. Yet up to 80% of cases of monogenic diabetes, a form of diabetes characterized by mutations in a single gene, are either overlooked or misdiagnosed. A genetic test for monogenic diabetes does not...
Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in COL2A1. Most of the variants found in patients with ACG2 affect the glycine residue included in the Gly-X-Y tripeptide repeat that characterizes t...
Duplications are the main type of dystrophin gene (DMD) variants, which typically cause dystrophinopathies such as Duchenne muscular dystrophy and Becker muscular dystrophy. Maternally inherited exon duplication in DMD in fetuses is a relatively comm...
Inherited retinal diseases (IRDs) are a diverse and variable group of rare human disorders [...]
Background and Clinical Significance: Methyltransferase-like protein 5 (METTL5) is a conserved RNA methyltransferase responsible for catalyzing the N6-methyladenosine (m6A) modification of 18S ribosomal RNA, a process critical for ribosome biogenesis...
Accurate interpretation of missense variants in cancer-associated genes remains a critical challenge in precision oncology, as most sequence-based predictors lack mechanistic explanations. Receptor tyrosine kinases like FGFR2 exemplify this problem:...
ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) are a family of multidomain extracellular protease enzymes with 19 members. A growing number of ADAMTS family gene variants have been identified in patients with various heredita...
Germline BRCA1/2 alteration has been linked to an increased risk of hereditary breast and ovarian cancer syndromes. As a result, genetic testing, based on NGS, allows us to identify a high number of variants of uncertain significance (VUS) or conflic...
Stickler syndrome (SS) is a hereditary connective tissue disorder affecting bones, eyes, and hearing. Type 2 SS and the SS variant otospondylomegaepiphyseal dysplasia (OSMED) are caused by deleterious variants in COL11A1 and COL11A2, respectively. In...
Lynch syndrome (LS) is one of the most common hereditary cancer predisposition syndromes worldwide. Individuals with LS have a high risk of developing colorectal or endometrial cancer, as well as several other cancers. LS is caused by autosomal domin...
Phenotypicheterogeneity is a phenomenon in which distinct phenotypes can develop in individuals bearing pathogenic variants in the same gene. Genetic factors, gene interactions, and environmental factors are usually considered the key mechanisms of t...
Background: Complex cases of retinoblastoma (RB) often require integrative molecular approaches to define tumor etiology and guide clinical management. Purpose: Our aim was to evaluate the usefulness of combining aqueous humor (AH)/plasma cell-free D...
Background: Cardiovascular diseases remain a leading cause of death worldwide, yet the prevalence of pathogenic and likely pathogenic genetic variants associated with them is still underassessed in some populations. This study aimed to assess the fre...
Defects in pre-mRNA splicing are frequently a cause of Mendelian disease. Despite the advent of next-generation sequencing, allowing a deeper insight into a patient’s variant landscape, the ability to characterize variants causing splicing defe...
Within recent years, many precision cancer medicine initiatives have been developed. Most of these have focused on solid cancers, while the potential of precision medicine for patients with hematological malignancies, especially in the relapse situat...
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