Exome Sequencing as a Potential Diagnostic Adjunct in Sporadic Congenital Hydrocephalus.
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ABSTRACT:
SUBMITTER: Sullivan W
PROVIDER: S-EPMC7670396 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
| S-EPMC7871900 | biostudies-literature
Project description:ImportanceExome sequencing (ES) has been established as the preferred first line of diagnostic testing for certain neurodevelopmental disorders, such as global developmental delay and autism spectrum disorder; however, current recommendations are not specific to or inclusive of congenital hydrocephalus (CH).ObjectiveTo determine the diagnostic yield of ES in CH and whether ES should be considered as a first line diagnostic test for CH.Data sourcesPubMed, Cochrane Library, and Google Scholar were used to identify studies published in English between January 1, 2010, and April 10, 2023. The following search terms were used to identify studies: congenital hydrocephalus, ventriculomegaly, cerebral ventriculomegaly, primary ventriculomegaly, fetal ventriculomegaly, prenatal ventriculomegaly, molecular analysis, genetic cause, genetic etiology, genetic testing, exome sequencing, whole exome sequencing, genome sequencing, microarray, microarray analysis, and copy number variants.Study selectionEligible studies included those with at least 10 probands with the defining feature of CH and/or severe cerebral ventriculomegaly that had undergone ES. Studies with fewer than 10 probands, studies of mild or moderate ventriculomegaly, and studies using genetic tests other than ES were excluded. A full-text review of 68 studies was conducted by 2 reviewers. Discrepancies were resolved by consensus.Data extraction and synthesisPreferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Meta-Analysis of Observational Studies in Epidemiology guidelines were used by 2 reviewers to extract data. Data were synthesized using a random-effects model of single proportions. Data analysis occurred in April 2023.Main outcomes and measuresThe primary outcome was pooled diagnostic yield. Additional diagnostic yields were estimated for specific subgroups on the basis of clinical features, syndromic presentation, and parental consanguinity. For each outcome, a 95% CI and estimate of interstudy heterogeneity (I2 statistic) was reported.ResultsFrom 498 deduplicated and screened records, 9 studies with a total of 538 CH probands were selected for final inclusion. The overall diagnostic yield was 37.9% (95% CI, 20.0%-57.4%; I2 = 90.1). The yield was lower for isolated and/or nonsyndromic cases (21.3%; 95% CI, 12.8%-31.0%; I2 = 55.7). The yield was higher for probands with reported consanguinity (76.3%; 95% CI, 65.1%-86.1%; I2 = 0) than those without (16.2%; 95% CI, 12.2%-20.5%; I2 = 0).Conclusions and relevanceIn this systematic review and meta-analysis of the diagnostic yield of ES in CH, the diagnostic yield was concordant with that of previous recommendations for other neurodevelopmental disorders, suggesting that ES should also be recommended as a routine diagnostic adjunct for patients with CH.
| S-EPMC10665979 | biostudies-literature
Project description:BackgroundCongenital vertical talus (CVT), also known as "rocker-bottom foot", is a rare foot deformity associated with a dislocation of the talonavicular joint. Although genetic causes of CVT have been described in single isolated and syndromic families, whole-exome sequencing (WES) of large cohorts have not yet been reported.MethodsIn this study, 62 probands with CVT were evaluated for likely causative single nucleotide variants (SNVs) and copy number variants (CNVs) using WES. Segregation of variants within families was determined by Sanger sequencing.ResultsIn this cohort, CVT occurred as an isolated anomaly in 75.8% (47/62) and was familial in 19.3% (12/62) of cases. Analysis of WES data led to the identification of likely causative variants in known disease genes in 30.6% (19/62) of all CVT probands. More than one proband had likely causative SNVs in TSHZ1, GDF5, and LMX1B. Only two probands had likely causative CNVs: a chromosome 12q13.13 deletion of the 5' HOXC gene cluster, and a chromosome 18q22.3q23 deletion involving TSHZ1. Familial CVT was strongly predictive of identifying a molecular diagnosis [75% (9/12) of familial cases compared to 20% (10/50) of non-familial cases (Chi-square test, P-value = 0.0002)]. There was no difference in the solved rate based on isolated or syndromic presentation, unilateral or bilateral affectation, or sex.ConclusionsCVT is genetically heterogeneous and more often caused by SNVs than CNVs. There is a high yield of WES in familial CVT cases (∼75%). Additional research is needed to identify the causes of sporadic CVT, which had much lower solved rates.
| S-EPMC10039454 | biostudies-literature
Project description:Leber congenital amaurosis (LCA) is a hereditary retinal dystrophy with wide genetic heterogeneity. Next-generation sequencing (NGS) targeting multiple genes can be a good option for the diagnosis of LCA, and we tested a clinical exome panel in patients with LCA.A total of nine unrelated Korean patients with LCA were sequenced using the Illumina TruSight One panel, which targets 4,813 clinically associated genes, followed by confirmation using Sanger sequencing. Patients' clinical information and familial study results were obtained and used for comprehensive interpretation.In all nine patients, we identified pathogenic variations in LCA-associated genes: NMNAT1 (n=3), GUCY2D (n=2), RPGRIP1 (n=2), CRX (n=1), and CEP290 or SPATA7. Six patients had one or two mutations in accordance with inheritance patterns, all consistent with clinical phenotypes. Two patients had only one pathogenic mutation in recessive genes (NMNAT1 and RPGRIP1), and the clinical features were specific to disorders associated with those genes. Six patients were solved for genetic causes, and it remains unclear for three patients with the clinical exome panel. With subsequent targeted panel sequencing with 113 genes associated with infantile nystagmus syndrome, a likely pathogenic allele in CEP290 was detected in one patient. Interestingly, one pathogenic variant (p.Arg237Cys) in NMNAT1 was present in three patients, and it had a high allele frequency (0.24%) in the general Korean population, suggesting that NMNAT1 could be a major gene responsible for LCA in Koreans.We confirmed that a commercial clinical exome panel can be effectively used in the diagnosis of LCA. Careful interpretation and clinical correlation could promote the successful implementation of clinical exome panels in routine diagnoses of retinal dystrophies, including LCA.
| S-EPMC5610811 | biostudies-literature
Project description:BackgroundCongenital hydrocephalus (CH) is a highly morbid disease that features enlarged brain ventricles and impaired cerebrospinal fluid homeostasis. Although early linkage or targeted sequencing studies in large multigenerational families have localized several genes for CH, the etiology of most CH cases remains unclear. Recent advances in whole exome sequencing (WES) have identified five new bona fide CH genes, implicating impaired regulation of neural stem cell fate in CH pathogenesis. Nonetheless, in the majority of CH cases, the pathological etiology remains unknown, suggesting more genes await discovery.MethodsWES of family members of a sporadic and familial form of severe L1CAM mutation-negative CH associated with aqueductal stenosis was performed. Rare genetic variants were analyzed, prioritized, and validated. De novo copy number variants (CNVs) were identified using the XHMM algorithm and validated using qPCR. Xenopus oocyte experiments were performed to access mutation impact on protein function and expression.ResultsA novel inherited protein-damaging mutation (p.Pro605Leu) in SLC12A6, encoding the K+ -Cl- cotransporter KCC3, was identified in both affected members of multiplex kindred CHYD110. p.Pro605 is conserved in KCC3 orthologs and among all human KCC paralogs. The p.Pro605Leu mutation maps to the ion-transporting domain, and significantly reduces KCC3-dependent K+ transport. A novel de novo CNV (deletion) was identified in SLC12A7, encoding the KCC3 paralog and binding partner KCC4, in another family (CHYD130) with sporadic CH.ConclusionThese findings identify two novel, related genes associated with CH, and implicate genetically encoded impairments in ion transport for the first time in CH pathogenesis.
| S-EPMC6732308 | biostudies-literature
Project description: Not available
| S-EPMC10479214 | biostudies-literature
Project description:Congenital hydrocephalus (CH) is a severe birth defect, and genetics components is an important etiology. Whole-exome sequencing (WES) has been proven to be a feasible approach for prenatal diagnosis of CH. In this study, we carried out WES on three fetuses with cerebral ventriculomegaly. After bioinformation analysis and data filtering, three compound variants, c.919C>T(p.Arg307Ter)/c.1100del(p.Phe369fs) in FKTN, c.1449_1450insACAACG/c.1490G>C(p.Arg497Pro) in POMGNT1, and c.2690+1G>A/c.1447C>T(p.Arg483Cys) in LAMB1 were detected in the three fetuses. All the six variants were classified as likely pathogenic or pathogenic in accordance with the American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines. This study provides support for the potential of WES for the accurate prenatal diagnosis of fetal hydrocephalus and further demonstrated the genetic heterogeneity in patients with CH. The novel variants (c.1449_1450insACAACG and c.1490G>C in POMGNT1, c.2690+1G>A in LAMB1) expanded the gene mutational spectrum of CH and contributes to genetics counseling and pregnancy management.
| S-EPMC9796612 | biostudies-literature
Project description:Genetic abnormalities, such as those of multiple endocrine neoplasia type 1 (MEN1) and Cyclin D1 (CCND1) genes, occur in <50% of nonhereditary (sporadic) parathyroid adenomas.To identify genetic abnormalities in nonhereditary parathyroid adenomas by whole-exome sequence analysis.Whole-exome sequence analysis was performed on parathyroid adenomas and leukocyte DNA samples from 16 postmenopausal women without a family history of parathyroid tumors or MEN1 and in whom primary hyperparathyroidism due to single-gland disease was cured by surgery. Somatic variants confirmed in this discovery set were assessed in 24 other parathyroid adenomas.Over 90% of targeted exons were captured and represented by more than 10 base reads. Analysis identified 212 somatic variants (median eight per tumor; range, 2-110), with the majority being heterozygous nonsynonymous single-nucleotide variants that predicted missense amino acid substitutions. Somatic MEN1 mutations occurred in six of 16 (?35%) parathyroid adenomas, in association with loss of heterozygosity on chromosome 11. However, no other gene was mutated in more than one tumor. Mutations in several genes that may represent low-frequency driver mutations were identified, including a protection of telomeres 1 (POT1) mutation that resulted in exon skipping and disruption to the single-stranded DNA-binding domain, which may contribute to increased genomic instability and the observed high mutation rate in one tumor.Parathyroid adenomas typically harbor few somatic variants, consistent with their low proliferation rates. MEN1 mutation represents the major driver in sporadic parathyroid tumorigenesis although multiple low-frequency driver mutations likely account for tumors not harboring somatic MEN1 mutations.
| S-EPMC4446457 | biostudies-literature
Project description:Fetal structural congenital abnormalities (SCAs) complicate 2-3% of all pregnancies. Whole-exome sequencing (WES) has been increasingly adopted prenatally when karyotyping and chromosomal microarray do not yield a diagnosis. This is a retrospective cohort study of 104 fetuses with SCAs identified on antenatal ultrasound in Hong Kong, where whole exome sequencing is performed. Molecular diagnosis was obtained in 25 of the 104 fetuses (24%). The highest diagnostic rate was found in fetuses with multiple SCAs (29.2%), particularly those with involvement of the cardiac and musculoskeletal systems. Variants of uncertain significance were detected in 8 out of the 104 fetuses (7.7%). Our study shows the utility of WES in the prenatal setting, and the extended use of the technology would be recommended in addition to conventional genetic workup.
| S-EPMC9778831 | biostudies-literature
Project description:PurposeHyperparathyroidism is the third most common endocrine disease. Parathyroid adenoma (PA) accounts for approximately 85% of cases of primary hyperparathyroidism, but the molecular mechanism is not fully understood. Herein, we aimed to investigate the genetic and transcriptomic profiles of sporadic PA.MethodsWhole-exome sequencing (WES) and transcriptome sequencing (RNA-seq) of 41 patients with PA and RNA-seq of 5 normal parathyroid tissues were performed. Gene mutations and characterized expression changes were identified. To elucidate the molecular mechanism underlying PA, unsupervised consensus clustering of RNA-seq data was performed. The correlations between the sequencing data and clinicopathological features of these patients were analyzed.ResultsPreviously reported PA driver gene mutations, such as MEN1 (9/41), mTOR (4/41), ZFX (3/41), CASR (3/41), EZH2 (2/41) and FAT1 (2/41), were also identified in our cohort. Furthermore, somatic mutation of EZH1, which had not been reported in PA, was found in 4 samples. RNA-seq showed that the expression levels of 84 genes were upregulated and 646 were downregulated in PA samples compared with normal samples. Unsupervised clustering analysis of RNA-seq data clustered these patients into 10 subgroups related to mutation or abnormal expression of a group of potential pathogenic genes.ConclusionMEN1, EZH2, CASR, EZH1, ZFX, mTOR and FAT1 mutations in PA were revealed. According to the RNA-seq data clustering analysis, cyclin D1, β-catenin, VDR, CASR and GCM2 may be important factors contributing to the PA gene expression profile.
| S-EPMC8163014 | biostudies-literature