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The Journal of Molecular Diagnostics :... Jun 2024Targeted tumor only sequencing has become a standard practice in cancer diagnostics. This study aims to develop an approach for robust copy number variant calling in...
Targeted tumor only sequencing has become a standard practice in cancer diagnostics. This study aims to develop an approach for robust copy number variant calling in tumor samples using only off-target region (OTR) reads. We also established a clinical use case for homologous recombination deficiency (HRD) score estimation (HRDest) using the sum of telomeric-allelic imbalance and large-scale state transition scores without the need for loss of heterozygosity information. A strong correlation was found between HRD score and the sum of telomeric-allelic imbalance + large-scale state transition in The Cancer Genome Atlas cohort (ρ = 0.99, P < 2.2 × 10) and in a clinical in-house cohort of 34 tumors (ρ = 0.9, P = 5.1 × 10) comparing whole-exome sequencing and targeted sequencing data. HRDest scores from 1086 clinical cases were compared with The Cancer Genome Atlas data set. There were no significant differences in HRD score distribution within the analyzed tumor types. As a control, commercially available HRD standards were also sequenced, and the HRDest scores obtained from the OTR reads were well within the HRD reference range provided by the manufacturer. In conclusion, OTR reads of tumor-only panel sequencing can be used to determine genome-wide copy number variant profiles and to approximate HRD scores.
Topics: Humans; Neoplasms; DNA Copy Number Variations; Exome Sequencing; High-Throughput Nucleotide Sequencing; Recombinational DNA Repair; Allelic Imbalance
PubMed: 38522840
DOI: 10.1016/j.jmoldx.2024.02.008 -
Human Genomics Mar 2024Chromosomal structural rearrangements consist of anomalies in genomic architecture that may or may not be associated with genetic material gain and loss. Evaluating the...
Chromosomal structural rearrangements consist of anomalies in genomic architecture that may or may not be associated with genetic material gain and loss. Evaluating the precise breakpoint is crucial from a diagnostic point of view, highlighting possible gene disruption and addressing to appropriate genotype-phenotype association. Structural rearrangements can either occur randomly within the genome or present with a recurrence, mainly due to peculiar genomic features of the surrounding regions. We report about three non-related individuals, harboring chromosomal structural rearrangements interrupting SETBP1, leading to gene haploinsufficiency. Two out of them resulted negative to Chromosomal Microarray Analysis (CMA), being the rearrangement balanced at a microarray resolution. The third one, presenting with a complex three-chromosome rearrangement, had been previously diagnosed with SETBP1 haploinsufficiency due to a partial gene deletion at one of the chromosomal breakpoints. We thoroughly characterized the rearrangements by means of Optical Genome Mapping (OGM) and Whole Genome Sequencing (WGS), providing details about the involved sequences and the underlying mechanisms. We propose structural variants as a recurrent event in SETBP1 haploinsufficiency, which may be overlooked by laboratory routine genomic analyses (CMA and Whole Exome Sequencing) or only partially determined when associated with genomic losses at breakpoints. We finally introduce a possible role of SETBP1 in a Noonan-like phenotype.
Topics: Humans; Haploinsufficiency; Chromosome Aberrations; Gene Rearrangement; Chromosomes; Whole Genome Sequencing; Carrier Proteins; Nuclear Proteins
PubMed: 38520002
DOI: 10.1186/s40246-024-00600-0 -
Nature Communications Mar 2024Subclonal copy number alterations are a prevalent feature in tumors with high chromosomal instability and result in heterogeneous cancer cell populations with distinct...
Subclonal copy number alterations are a prevalent feature in tumors with high chromosomal instability and result in heterogeneous cancer cell populations with distinct phenotypes. However, the extent to which subclonal copy number alterations contribute to clone-specific phenotypes remains poorly understood. We develop TreeAlign, which computationally integrates independently sampled single-cell DNA and RNA sequencing data from the same cell population. TreeAlign accurately encodes dosage effects from subclonal copy number alterations, the impact of allelic imbalance on allele-specific transcription, and obviates the need to define genotypic clones from a phylogeny a priori, leading to highly granular definitions of clones with distinct expression programs. These improvements enable clone-clone gene expression comparisons with higher resolution and identification of expression programs that are genomically independent. Our approach sets the stage for dissecting the relative contribution of fixed genomic alterations and dynamic epigenetic processes on gene expression programs in cancer.
Topics: Humans; DNA Copy Number Variations; Alleles; Neoplasms; Genotype; Phenotype
PubMed: 38509111
DOI: 10.1038/s41467-024-46710-0 -
Blood Cancer Journal Mar 2024
Topics: Humans; Lenalidomide; Myelodysplastic Syndromes; Thalidomide; Mutation; Clonal Evolution; Chromosomes, Human, Pair 5; Chromosome Deletion
PubMed: 38499527
DOI: 10.1038/s41408-024-01027-5 -
Taiwanese Journal of Obstetrics &... Mar 2024
Topics: Pregnancy; Female; Humans; Cri-du-Chat Syndrome; Chromosomes, Human, Pair 5; Prenatal Diagnosis; Chromosome Aberrations; Cytogenetic Analysis; Fetus; Chromosome Deletion; Amniocentesis
PubMed: 38485330
DOI: 10.1016/j.tjog.2024.01.029 -
Taiwanese Journal of Obstetrics &... Mar 2024Kleefstra syndrome (KS), formerly known as 9q subtelomeric deletion syndrome, is characterized by multiple structural abnormalities. However, most fetuses do not have...
OBJECTIVE
Kleefstra syndrome (KS), formerly known as 9q subtelomeric deletion syndrome, is characterized by multiple structural abnormalities. However, most fetuses do not have obvious abnormal phenotypes. In this study, the fetus with KS presented with multiple system structural anomalies, and we aimed to explore the genotype-phenotype correlations of KS fetuses.
CASE REPORT
Multiple systematic structural anomalies, including severe intrauterine growth restriction (IUGR) and cardiac defects, were detected by ultrasound in the fetus at 33 + 5 weeks' gestation. These abnormalities may be caused by the pathogenic deleted fragment at 9q34.3, including the euchromatic histone methyltransferase 1 (EHMT1) and collagen type V alpha 1 chain (COL5A1) genes, detected by copy number variation sequencing (CNV-seq).
CONCLUSIONS
It is essential for clinicians to perform CNV-seq combined with multidisciplinary consultation for suspected KS fetuses, especially those with multiple systematic structural anomalies.
Topics: Humans; DNA Copy Number Variations; Heart Defects, Congenital; Chromosome Deletion; Intellectual Disability; Abnormalities, Multiple; Fetus; Genetic Association Studies; Chromosomes, Human, Pair 9; Craniofacial Abnormalities
PubMed: 38485322
DOI: 10.1016/j.tjog.2024.01.021 -
Frontiers in Endocrinology 2024Analyze the relationship between changes in the proportion of X-chromosome deletions and clinical manifestations in children with Turner syndrome (TS).
PURPOSE
Analyze the relationship between changes in the proportion of X-chromosome deletions and clinical manifestations in children with Turner syndrome (TS).
METHODS
X-chromosome number abnormalities in 8,635 children with growth retardation were identified using fluorescence hybridization (FISH). Meanwhile, the relationship between the proportion of X-chromosome deletions and the clinical manifestations of TS, such as face and body phenotype, cardiovascular, renal, and other comorbidities in children with TS was analyzed.
RESULTS
A total of 389 children had X-chromosome number abnormalities, with an average age at diagnosis of 9.2 years. There was a significant increase in diagnoses around the ages of 3 and 7 years and highest number of diagnoses at 10 years of age. 130 with XO (complete loss of an X-chromosome), 205 with XO/XX, 8 with XO/XXX, 23 with XO/XX/XXX, 19 with XO/XY, and 4 with XO/XY/XYY. Body and facial phenotypes increased with higher mosaicism proportions, with a relatively high correlation shown with Pearson correlation analysis ( = 0.26, = 1.7e-06). The incidence of congenital heart malformations was 25.56%, mainly involving a bicuspid aortic valve, and were more common in patients who had complete loss of an X-chromosome. However, this relationship was not present for renal disease ( = 0.26), central nervous system, thyroid, or liver disease.
CONCLUSION
The mosaicism (XO/XX) is the most common karyotype of TS in screened cases. The phenotypes in children with TS may increase with the proportion of X-chromosome deletions, but the renal disease and comorbidities did not show the same characteristics.
Topics: Child; Humans; Turner Syndrome; Chromosome Deletion; In Situ Hybridization, Fluorescence; Chromosomes, Human, X; Karyotyping; Kidney Diseases
PubMed: 38481442
DOI: 10.3389/fendo.2024.1324160 -
BMC Psychology Mar 202416p11.2 proximal deletion and duplication syndromes (Break points 4-5) (593KB, Chr16; 29.6-30.2mb - HG38) are observed to have highly varied phenotypes, with a known...
BACKGROUND
16p11.2 proximal deletion and duplication syndromes (Break points 4-5) (593KB, Chr16; 29.6-30.2mb - HG38) are observed to have highly varied phenotypes, with a known propensity for lifelong psychiatric problems. This study aimed to contribute to a research gap by qualitatively exploring the challenges families with 16p11.2 deletion and duplication face by answering three research questions: (1) What are parents' perceptions of the ongoing support needs of families with children who have 16p11.2 living in the UK?; (2) What are their experiences in trying to access support?; (3) In these regards, do the experiences of parents of children with duplication converge or vary from those of parents of children with 16p11.2 deletion?
METHODS
33 parents with children (aged 7-17 years) with 16p11.2 deletion or duplication participated in structured interviews, including the Autism Diagnostic Interview- Revised (ADI-R). Their answers to the ADI-R question 'what are your current concerns' were transcribed and subsequently analysed using Braun and Clarke's six step reflexive thematic analysis framework.
RESULTS
Three themes were identified: (1) Child is Behind Peers (subthemes: developmentally; academically; socially; emotionally); (2) Metabolism and Eating Patterns and; (3) Support (subthemes: insufficient support available; parent has to fight to access support; COVID-19 was a barrier to accessing support; 16p11.2 diagnosis can be a barrier to support, child is well-supported).
CONCLUSIONS
Parents of children with either 16p11.2 deletion or duplication shared similar experiences. However, metabolism concerns were specific to parents of children with 16p11.2 deletion. The theme Child is Behind Peers echoed concerns raised in previous Neurodevelopmental Copy Number Variant research. However, there were some key subthemes relating to research question (2) which were specific to this study. This included parents' descriptions of diagnostic overshadowing and the impact of a lack of eponymous name and scant awareness of 16p11.2.
Topics: Child; Humans; Chromosome Deletion; Autistic Disorder; Parents
PubMed: 38475925
DOI: 10.1186/s40359-024-01609-9 -
Diagnostics (Basel, Switzerland) Feb 2024Pancreatic cystic disease, including duct dilation, represents precursor states towards the development of pancreatic cancer, a form of malignancy with relatively low...
Pancreatic cystic disease, including duct dilation, represents precursor states towards the development of pancreatic cancer, a form of malignancy with relatively low incidence but high mortality. While most of these cysts (>85%) are benign, the remainder can progress over time, leading to malignant transformation, invasion, and metastasis. Cytologic diagnosis is challenging, limited by the paucity or complete absence of cells representative of cystic lesions and fibrosis. Molecular analysis of fluids collected from endoscopic-guided fine-needle aspiration of pancreatic cysts and dilated duct lesions can be used to evaluate the risk of progression to malignancy. The basis for the enhanced diagnostic utility of molecular approaches is the ability to interrogate cell-free nucleic acid of the cyst/duct and/or extracellular fluid. The allelic imbalances at tumor suppressor loci and the selective oncogenic drivers are used clinically to help differentiate benign stable pancreatic cysts from those progressing toward high-grade dysplasia. Methods are discussed and used to determine the efficacy for diagnostic implementation. Here, we report the analytical validation of methods to detect causally associated molecular changes integral to the pathogenesis of pancreatic cancer from pancreatic cyst fluids.
PubMed: 38472986
DOI: 10.3390/diagnostics14050514 -
Cancer Cell Apr 2024SMARCA4 encodes one of two mutually exclusive ATPase subunits in the BRG/BRM associated factor (BAF) complex that is recruited by transcription factors (TFs) to drive...
SMARCA4 encodes one of two mutually exclusive ATPase subunits in the BRG/BRM associated factor (BAF) complex that is recruited by transcription factors (TFs) to drive chromatin accessibility and transcriptional activation. SMARCA4 is among the most recurrently mutated genes in human cancer, including ∼30% of germinal center (GC)-derived Burkitt lymphomas. In mice, GC-specific Smarca4 haploinsufficiency cooperated with MYC over-expression to drive lymphomagenesis. Furthermore, monoallelic Smarca4 deletion drove GC hyperplasia with centroblast polarization via significantly increased rates of centrocyte recycling to the dark zone. Mechanistically, Smarca4 loss reduced the activity of TFs that are activated in centrocytes to drive GC-exit, including SPI1 (PU.1), IRF family, and NF-κB. Loss of activity for these factors phenocopied aberrant BCL6 activity within murine centrocytes and human Burkitt lymphoma cells. SMARCA4 therefore facilitates chromatin accessibility for TFs that shape centrocyte trajectories, and loss of fine-control of these programs biases toward centroblast cell-fate, GC hyperplasia and lymphoma.
Topics: Animals; Humans; Mice; Chromatin; DNA Helicases; Haploinsufficiency; Hyperplasia; Lymphoma, B-Cell; Nuclear Proteins; Transcription Factors
PubMed: 38458188
DOI: 10.1016/j.ccell.2024.02.011