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Molecular genetic analysis of pulmonary benign metastasizing leiomyoma and intravenous leiomyomatosis: a comparative study using whole exome sequencing.

OBJECTIVE: Benign Metastasizing Leiomyoma (BML) and Intravenous Leiomyomatosis (IVL) are rare uterine-derived smooth muscle tumors. Although both exhibit histologically benign and similar features, they demonstrate aggressive biological behaviors. Currently, molecular genetic studies on BML and IVL are limited, and no comparative research on their genetic variations has been reported. To investigate the genetic basis underlying their shared aggressive phenotypes, this study employs whole-exome sequencing (WES) to conduct a molecular genetic comparison between the two entities. The aim is to ex…

Exome and transcriptome analysis link calcium channel pathway aberrations to botulinum toxin A resistance in Hailey-Hailey disease.

BACKGROUND: The effectiveness of botulinum toxin A (BoNTA) in the treatment of Hailey-Hailey disease (HHD) has shown heterogeneity in recent … obal Assessment(IGA) from baseline to month 6. A comprehensive multiomics approach, including whole-exome sequencing (WES), bulk RNA sequencing (RNAseq), single-cell RNAseq and immunohistochemistry (IHC) was used to investigate potential mechanisms underlying the heterogeneity of therapeutic efficacy. Additionally, an in vitro experiment was conducted t …

Анализ многократной миеломы (ММ) и Моноклональной гаммопатии неопределенных знаков (MGUS)

История семьи является известным фактором риска для множественной миеломы (ММ) и ее предшественника, моноколональной гаммопатии неопределённого значения (МГУС). Предыдущие исследования в рамках всей ассоциации генома (ОСГ) выявили 35 общие loci, связанные с риском MM и 21 связанные с MGS. Цель этого исследования заключалась в выявлении менее распространенных и редких генетических loci, предвосхищающих MM/MGUS, путем проведения анализа последовательности связей на основе целых экспозиций (WES).МЕТОДЫ: Мультиточечный анализ связей был проведен с использованием многоточечного двигателя быстрого с

Совпадение в аннотации оригинала
BACKGROUND/OBJECTIVES: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of … this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis. METHODS: Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander-Green algorithm on germline WES data from 79 pedigrees with 2 or more af …

Whole-exome sequencing of individuals from an isolated population under extreme conditions implicates rare risk variants of schizophrenia.

Schizophrenia (SCZ), which affects approximately 1% of the world's population, is a global public health concern. It is generally considered that the interplay between genes and the environment is important in the onset and/or development of SCZ. Although several whole-exome sequencing studies have revealed rare risk variants of SCZ, no rare coding variants have been strongly replicated. Assessing isolated populations under extreme conditions might lead to the discovery of variants with a recent origin, which are more likely to have a higher frequency than chance to reflect gene-environment in…

Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy su…

Genetic Variants in Severe Hypertriglyceridemia Among Taiwanese Participants　- Insights From Genome-Wide Association and Whole-Exome Sequencing Analyses.

BACKGROUND: There are limited data on the use of whole-exome sequencing (WES) to diagnose severe hypertriglyceridemia. Our aim was to identify candidate genes linked to triglyceride levels via a genome-wide association study (GWAS) and to recruit participants with severe hypertriglyceridemia for WES to assess allelic variants in the candidate genes. METHODS AND RESULTS: A GWAS was conducted involving 120,140 participants to identify lead loci associated with blood triglyceride levels. Following the identification of these lead loci, WES was performed on DNA samples from 29 participants with h…

Semiautomated approach focused on new genomic information results in time and effort-efficient reannotation of negative exome data.

Most rare disease patients (75-50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identified. Data review over time can leverage novel information regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting. We developed RENEW, (REannotation of NEgative WES/WGS) an automated reannotation procedure that uses relevant new information in on-line genomic databases to enable rapid review of genomic findings. We tested RE

Exome Sequencing to Identify Novel Variants Associated with Secondary Amenorrhea and Premature Ovarian Insufficiency (POI) in Saudi Women.

BACKGROUND AND OBJECTIVES: Post-pubertal disappearance of menstrual cycles (secondary amenorrhea) associated with premature follicular deple … yndrome (PCOS) was excluded by using Rotterdam consensus criteria. Patients' DNA samples were whole-exome sequenced (WES). Bidirectional Sanger sequencing was then utilized to validate the identified candidate variants. The pathogenicity of detected variants was predicted using several types of bioinformatics software. RESULTS: Most of the patients hav …

Clinical whole Exome Sequencing Reveals Novel Homozygous Missense Variant in the PMPCA Gene causing Autosomal Recessive Spinocerebellar Ataxia.

BACKGROUND & OBJECTIVE: Autosomal recessive cerebellar ataxias (ARCA) are rare heterogenous neurodegenerative disorders characterized by degeneration of the cerebellum and spinal cord with an early onset before the age of 20 years. PMPCA (MIM: 613036), is a key enzyme in mitochondrial protein processing which is critical for cell survival and growth. Our objective was to investigate Peptidase, Mitochondrial Processing Subunit Alpha (PMPCA) mutations linked with Spinocerebellar ataxia, autosomal recessive 2 (SCAR2). METHOD: In the current study, Whole Exome Sequencing (WES) was done followed b…

Whole-exome-based single nucleotide variants and copy number analysis for prenatal diagnosis of compound heterozygosity of SMPD4.

BACKGROUND: Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder. These variants have been ident … s, the parallel detection of copy number variants (CNVs) and single nucleotide variants using whole-exome analysis is required. A physical examination of the parents was performed. Karyotype and whole-exome analysis were performed for the fetus and the parents. RESULTS: A fetus with microcephaly and arthrogryposis; biallelic null variants (c.387-1G>A; …

Exome Sequencing in Fetuses With Bilateral Renal Agenesis Identified on Second Trimester Ultrasound: A Single Referral Center Experience.

OBJECTIVE: To determine the exome sequencing results in fetuses with bilateral renal agenesis (BRA). METHODS: This was a retrospective study of 14 cases with BRA diagnosed on second trimester anatomy ultrasound. All cases underwent invasive prenatal diagnosis. Genetic investigations were performed by chromosomal microarray analysis and trio exome sequencing. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, molecular sequencing results, and pregnancy outcomes. RESULTS: Pathogenic and likely pathogenic var…

Large-scale whole-exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350,770 adults.

The genetic contribution of protein-coding variants to immune-mediated diseases (IMDs) remains underexplored. Through whole exome sequencing of 40 IMDs in 350,770 UK Biobank participants, we identified 162 unique genes in 35 IMDs, among which 124 were novel genes. Several genes, including FLG which is associated with atopic dermatitis and asthma, showed converging evidence from both rare and common variants. 91 genes exerted significant effects on longitudinal outcomes (interquartile range of Hazard Ratio: 1.12-5.89). Mendelian randomization identified five causal genes, of which four were app…

Whole exome sequencing of a novel homozygous missense variant in PALB2 gene leading to Fanconi anaemia complementation group.

Partner and localiser of BRCA2 (PALB2), also known as FANCN, is a key tumour suppressor gene in maintaining genome integrity. Monoallelic mutations of PALB2 are associated with breast and overian cancers, while bi-allelic mutations cause Fanconi anaemia (FA). In the present study, whole exome sequencing (WES) identified a novel homozygous missense variant, NM_024675.3: c.3296C>G (p.Thr1099Arg) in PALB2 gene (OMIM: 610355) that caused FA with mild pulmonary valve stenosis and dysmorphic and atypical features, including lymphangiectasia, non-immune hydrops fetalis and right-sided pleural effusio…

Clinical phenotype and trio whole exome sequencing data from a patient with glycogen storage disease IV in Indonesia.

Glycogen storage disease type IV (GSD IV) is a rare disease caused by a defect in glycogen branching enzyme 1 (GBE1), which played a crucial … ariants requiring further functional studies to confirm their pathogenicity. Proband and trio whole exome sequencing analysis remains a cost-effective and widely available method for diagnosing rare diseases detecting between 21 and 40% of cases. We present a trio (familial) exome sequences data from a patient with Glycogen Storage Disease IV from Indon …

Streamlined two-step fragment analysis PCR and exome sequencing of RFC1 for diagnostic testing of suspected CANVAS patients.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is caused by biallelic pathogenic expansions, or compound heterozy … hort-allele screening PCR and a confirmatory PCR with fragment capillary electrophoresis detection. Exome sequencing of RFC1 was additionally foreseen to resolve potential compound heterozygosity cases. Specificity of our approach was evaluated using ataxia patients with known non-CANVAS diagnoses, and optimized using Southern blot confirmed CANVAS pati …

Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting.

Although several studies have explored the molecular landscape of metastatic melanoma, the genetic determinants of therapy resistance are still largely unknown. Here, we aimed to determine the contribution of whole-exome sequencing and circulating free DNA (cfDNA) analysis in predicting response to therapy in a consecutive real-world cohort of 36 patients, undergoing fresh tissue biopsy and followed during treatment. Although the underpowered sample size limited statistical analysis, samples from non-responders had higher copy number variations and mutations in melanoma driver genes compared t…

Comparing rare variants versus common in the pathogenesis of nonalcoholic fatty liver disease: a whole exome sequencing approach.

BACKGROUND/PURPOSE: Genome-wide association studies have reported the association of common variants with nonalcoholic fatty liver disease in genes, namely, PNPLA3/TM6SF2/MBOAT7/HSD17B13, across ethnicities. However, the approach does not identify rarer variants with a higher effect size. We therefore sequenced the complete exonic regions of patients with nonalcoholic steatohepatitis and controls to compare rare and common variants with a role in the pathogenesis. METHODS: This is a prospective study that recruited 54 individuals with/without fatty infiltration. Patients with biopsy-proven no

Whole Exome Sequencing Identified Two Single Nucleotide Polymorphisms of Human Leukocyte Antigen-DRB5 in Familial Sarcoidosis in China.

BACKGROUND: Sarcoidosis is a multisystem granulomatous disorder whose etiology is related to genetic and immunological factors. Familial aggregation and ethnic prevalence suggest a genetic predisposition and inherited susceptibility to sarcoidosis. OBJECTIVE: This study aimed to identify suspected risk loci for familial sarcoidosis patients. METHODS: We conducted whole exome sequencing on two sarcoidosis patients and five healthy family members in a Chinese family for a case-control study. The two sarcoidosis patients were siblings who showed chronic disease. RESULTS: The Gene Ontology resu…

Whole-Exome Sequencing Identified a Novel DYRK1A Variant in a Patient With Intellectual Developmental Disorder, Autosomal Dominant 7.

Intellectual developmental disorder, autosomal dominant 7 (MRD7; OMIM 614104) is a rare disease characterized by microcephaly, intellectual disability, speech delay, feeding difficulties, and facial dysmorphisms. This disorder is caused by pathogenic/likely pathogenic variants of the DYRK1A gene, which encodes dual-specificity tyrosine-phosphorylation-regulated kinase 1A. Here, we report a case of MRD7 that was diagnosed using Face2Gene and whole-exome sequencing (WES). A 22-year-old man presented with microcephaly, intellectual disability, slender body, long slender fingers, and facial dysmor…

Exome Survey and Candidate Gene Re-Sequencing Identifies Novel Exstrophy Candidate Genes and Implicates LZTR1 in Disease Formation.

BACKGROUND: The bladder exstrophy-epispadias complex (BEEC) is a spectrum of congenital abnormalities that involves the abdominal wall, the bony pelvis, the urinary tract, the external genitalia, and, in severe cases, the gastrointestinal tract as well. METHODS: Herein, we performed an exome analysis of case-parent trios with cloacal exstrophy (CE), the most severe form of the BEEC. Furthermore, we surveyed the exome of a sib-pair presenting with classic bladder exstrophy (CBE) and epispadias (E) only. Moreover, we performed large-scale re-sequencing of CBE individuals for novel candidate gen…