Large structural chromosomal deletions and duplications, referred to as copy number variants (CNVs), play a role in the pathogenesis of neurodevelopmental disorders (NDDs) through effects on gene ...dosage. This review focuses on our current understanding of genomic disorders that arise from large structural chromosome rearrangements in patients with NDDs, as well as difficulties in overlap of clinical presentation and molecular diagnosis. We discuss the implications of epigenetics, specifically DNA methylation (DNAm), in NDDs and genomic disorders, and consider the implications and clinical impact of copy number and genomic DNAm testing in patients with suspected genetic NDDs. We summarize evidence of global methylation episignatures in CNV-associated disorders that can be used in the diagnostic pathway and may provide insights into the molecular pathogenesis of genomic disorders. Finally, we discuss the potential for combining CNV and DNAm assessment into a single diagnostic assay.
Gender score is the cognitive judgement of the degree of masculinity or femininity of a face which is considered to be a continuum. Gender scores have long been used in psychological studies to ...understand the complex psychosocial relationships between people. Perceptual scores for gender and attractiveness have been employed for quality assessment and planning of cosmetic facial surgery. Various neurological disorders have been linked to the facial structure in general and the facial gender perception in particular. While, subjective gender scoring by human raters has been a tool of choice for psychological studies for many years, the process is both time and resource consuming. In this study, we investigate the geometric features used by the human cognitive system in perceiving the degree of masculinity/femininity of a 3D face. We then propose a mathematical model that can mimic the human gender perception. For our experiments, we obtained 3D face scans of 64 subjects using the 3dMDface scanner. The textureless 3D face scans of the subjects were then observed in different poses and assigned a gender score by 75 raters of a similar background. Our results suggest that the human cognitive system employs a combination of Euclidean and geodesic distances between biologically significant landmarks of the face for gender scoring. We propose a mathematical model that is able to automatically assign an objective gender score to a 3D face with a correlation of up to 0.895 with the human subjective scores.
The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans and is the result of a recurrent 1.5 to 2.5 Mb deletion, encompassing approximately 20–40 genes, respectively. ...The clinical presentation of the typical deletion includes: Velocardiofacial, Di George, Opitz G/BBB and Conotruncalanomaly face syndromes. Atypical deletions (proximal, distal or nested) are rare and characterized mainly by normal phenotype or mild intellectual disability and variable clinical features. The pathogenetic mechanisms underlying this disorder are not completely understood. Because the 22q11.2 region harbours genes coding for transcriptional factors and chromatin remodelers, in this study, we performed analysis of genome-wide DNA methylation of peripheral blood from 49 patients with 22q11.2DS using the Illumina Infinium Methylation EPIC bead chip arrays. This cohort comprises 43 typical, 2 proximal and 4 distal deletions. We demonstrated the evidence of a unique and highly specific episignature in all typical and proximal 22q11.2DS. The sensitivity and specificity of this signature was further confirmed by comparing it to over 1500 patients with other neurodevelopmental disorders with known episignatures. Mapping the 22q11.2DS DNA methylation episignature provides both novel insights into the molecular pathogenesis of this disorder and an effective tool in the molecular diagnosis of 22q11.2DS.
Clark-Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the
(Thyroid Hormone Receptor Interactor 12) gene.
encodes an E3 ligase in the ...ubiquitin pathway. The ubiquitin pathway includes activating E1, conjugating E2 and ligating E3 enzymes which regulate the breakdown and sorting of proteins. This enzymatic pathway is crucial for physiological processes. A significant proportion of
variants are currently classified as variants of unknown significance (VUS). Episignatures have been shown to represent a powerful diagnostic tool to resolve inconclusive genetic findings for Mendelian disorders and to re-classify VUSs. Here, we show the results of DNA methylation episignature analysis in 32 individuals with pathogenic, likely pathogenic and VUS variants in
. We identified a specific and sensitive DNA methylation (DNAm) episignature associated with pathogenic
variants, establishing its utility as a clinical biomarker for Clark-Baraitser syndrome. In addition, we performed analysis of differentially methylated regions as well as functional correlation of the
genome-wide methylation profile with the profiles of 56 additional neurodevelopmental disorders.
JARID2 (Jumonji, AT-rich interactive domain 2) haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. It is characterized by intellectual disability, developmental ...delay, autistic features, behavior abnormalities, cognitive impairment, hypotonia, and dysmorphic features. JARID2 acts as a transcriptional repressor protein that is involved in the regulation of histone methyltransferase complexes. JARID2 plays a role in the epigenetic machinery, and the associated syndrome has an identified DNA methylation episignature derived from sequence variants and intragenic deletions involving JARID2. For this study, our aim was to determine whether patients with larger deletions spanning beyond JARID2 present a similar DNA methylation episignature and to define the critical region involved in aberrant DNA methylation in 6p22–p24 microdeletions. We examined the DNA methylation profiles of peripheral blood from 56 control subjects, 13 patients with (likely) pathogenic JARID2 variants or patients carrying copy number variants, and three patients with JARID2 VUS variants. The analysis showed a distinct and strong differentiation between patients with (likely) pathogenic variants, both sequence and copy number, and controls. Using the identified episignature, we developed a binary model to classify patients with the JARID2-neurodevelopmental syndrome. DNA methylation analysis indicated that JARID2 is the driver gene for aberrant DNA methylation observed in 6p22–p24 microdeletions. In addition, we performed analysis of functional correlation of the JARID2 genome-wide methylation profile with the DNA methylation profiles of 56 additional neurodevelopmental disorders. To conclude, we refined the critical region for the presence of the JARID2 episignature in 6p22–p24 microdeletions and provide insight into the functional changes in the epigenome observed when regulation by JARID2 is lost.
JARID2 (Jumonji, AT Rich Interactive Domain 2) pathogenic variants cause a neurodevelopmental syndrome, that is characterized by developmental delay, cognitive impairment, hypotonia, autistic ...features, behavior abnormalities and dysmorphic facial features. JARID2 encodes a transcriptional repressor protein that regulates the activity of various histone methyltransferase complexes. However, the molecular etiology is not fully understood, and JARID2-neurodevelopmental syndrome may vary in its typical clinical phenotype. In addition, the detection of variants of uncertain significance (VUSs) often results in a delay of final diagnosis which could hamper the appropriate care. In this study we aim to detect a specific and sensitive DNA methylation signature for JARID2-neurodevelopmental syndrome. Peripheral blood DNA methylation profiles from 56 control subjects, 8 patients with (likely) pathogenic JARID2 variants and 3 patients with JARID2 VUSs were analyzed. DNA methylation analysis indicated a clear and robust separation between patients with (likely) pathogenic variants and controls. A binary model capable of classifying patients with the JARID2-neurodevelopmental syndrome was constructed on the basis of the identified episignature. Patients carrying VUSs clustered with the control group. We identified a distinct DNA methylation signature associated with JARID2-neurodevelopmental syndrome, establishing its utility as a biomarker for this syndrome and expanding the EpiSign diagnostic test.
Available for the first time in an English translation, this selection of René Magritte's writings gives non-Francophone readers the chance to encounter the many incarnations of the renowned Belgian ...painter-the artist, the man, the aspiring noirist, the fire-breathing theorist-in his own words. Through whimsical personal letters, biting apologia, appreciations of fellow artists, pugnacious interviews, farcical film scripts, prose poems, manifestos, and much more, a new Magritte emerges: part Surrealist, part literalist, part celebrity, part rascal.While this book is sure to appeal to admirers of Magritte's art and those who are curious about his personal life, there is also much to delight readers interested in the history and theory of art, philosophy and politics, as well as lovers of creativity and the inner workings of a probing, inquisitive mind unrestricted by genre, medium, or fashion.
Background
Hereditary cancer predisposition syndromes account for approximately 10% of cancer cases. Next generation sequencing (NGS) based multi-gene targeted panels is now a frontline approach to ...identify pathogenic mutations in cancer predisposition genes in high-risk families. Recent evolvement of NGS technologies have allowed simultaneous detection of sequence and copy number variants (CNVs) using a single platform. In this study, we have analyzed frequency and nature of sequence variants and CNVs, in a Canadian cohort of patients, suspected with hereditary cancer syndrome, referred for genetic testing following specific genetic testing guidelines based on patient’s personal and/or family history of cancer.
Methods
A 2870 patients were subjected to a single NGS based multi-gene targeted hereditary cancer panel testing algorithm to identify sequence variants and CNVs in cancer predisposition genes at our reference laboratory in Southwestern Ontario. CNVs identified by NGS were confirmed by alternative techniques like Multiplex ligation-dependent probe amplification (MLPA).
Results
A 15% (431/2870) patients had a pathogenic variant and 36% (1032/2870) had a variant of unknown significance (VUS), in a cancer susceptibility gene. A total of 287 unique pathogenic variant were identified, out of which 23 (8%) were novel. CNVs identified by NGS based approach accounted for 9.5% (27/287) of pathogenic variants, confirmed by alternate techniques with high accuracy.
Conclusion
This study emphasizes the utility of NGS based targeted testing approach to identify both sequence and CNVs in patients suspected with hereditary cancer syndromes in clinical setting and expands the mutational spectrum of high and moderate penetrance cancer predisposition genes.
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