Single-cell transcriptomics for the assessment of cardiac disease

Nature Reviews Cardiology, Journal Year: 2022, Volume and Issue: 20(5), P. 289 - 308

Published: Dec. 20, 2022

Language: Английский

---

Diagnostic Approach to Macrocephaly in Children

Frontiers in Pediatrics, Journal Year: 2022, Volume and Issue: 9

Published: Jan. 14, 2022

Macrocephaly affects up to 5% of the pediatric population and is defined as an abnormally large head with occipitofrontal circumference (OFC) >2 standard deviations (SD) above mean for a given age sex. Taking into account that about 2–3% healthy has OFC between 2 3 SD, macrocephaly considered “clinically relevant” when SD. This implies urgent need diagnostic workflow use in clinical setting dissect several causes increased OFC, from benign form familial Benign enlargement subarachnoid spaces (BESS) many pathological conditions, including genetic disorders. Moreover, should be differentiated by megalencephaly (MEG), which refers exclusively brain overgrowth, exceeding twice SD (3SD—“clinically megalencephaly). While can isolated or may first indication underlying congenital, genetic, acquired disorder, most likely due cause. Apart size evaluation, detailed family personal history, neuroimaging, careful evaluation are crucial reach correct diagnosis. In this review, we seek underline aspects megalencephaly, emphasizing main differential diagnosis major focus on common We thus provide clinico-radiological algorithm guide pediatricians assessment children macrocephaly.

Language: Английский

---

Neurodevelopmental disorders and cancer networks share pathways, but differ in mechanisms, signaling strength, and outcome

npj Genomic Medicine, Journal Year: 2023, Volume and Issue: 8(1)

Published: Nov. 4, 2023

Epidemiological studies suggest that individuals with neurodevelopmental disorders (NDDs) are more prone to develop certain types of cancer. Notably, however, the case statistics can be impacted by late discovery cancer in afflicted NDDs, such as intellectual disorders, autism, and schizophrenia, which may bias numbers. As NDD-associated mutations, most cases, they germline while mutations sporadic, emerging during life. However, somatic mosaicism spur cancer-related germline. NDDs share proteins, pathways, mutations. Here we ask (i) exactly features share, (ii) how, despite their commonalities, differ clinical outcomes. To tackle these questions, employed a statistical framework followed network analysis. Our thorough exploration reconstructed disease-specific networks, transcriptome levels profiles autism spectrum disorder (ASD) cancers, point signaling strength key factor: strong promotes cell proliferation cancer, weaker (moderate) impacts differentiation ASD. Thus, strength, not activating decide outcome.

Language: Английский

---

Beyond the Exome: The Non-coding Genome and Enhancers in Neurodevelopmental Disorders and Malformations of Cortical Development

Frontiers in Cellular Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: July 31, 2019

The development of the human cerebral cortex is a complex and dynamic process, in which neural stem cell proliferation, neuronal migration post-migratory organization need to occur well-organized fashion. Alterations at any these crucial stages can result Malformations Cortical Development (MCDs), group genetically heterogeneous neurodevelopmental disorders that present with developmental delay, intellectual disability epilepsy. Recent progress genetic technologies, such as next generation sequencing, most often focusing on all protein-coding exons (e.g., Whole Exome Sequencing), allowed discovery more than hundred genes associated various types MCDs. Although this has considerably increased diagnostic yield, MCD cases still remain unexplained. As Sequencing investigates only minor part genome (1-2%), it likely patients, no disease-causing mutation been identified, could harbor mutations genomic regions beyond exome. Even though functional annotation non-coding lagging behind genes, tremendous made field gene regulation. One regulatory are enhancers, be distantly located upstream or downstream mediate temporal tissue-specific transcriptional control via long-distance interactions promoter regions. some examples exist literature link alterations enhancers disorders, widespread appreciation putative roles sequences MCDs lacking. Here, we summarize current state knowledge cis-regulatory discuss novel technologies massively-parallel reporter assay systems, CRISPR-Cas9-based screens computational approaches help further elucidate emerging role disease. Moreover, existing copy number involved brain development. We foresee future implementation obtained through ongoing regulation studies will benefit patients provide an explanation missing heritability other disorders.

Language: Английский

---

A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing

Genome Medicine, Journal Year: 2019, Volume and Issue: 11(1)

Published: July 26, 2019

Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of detected by exome diverse indications performed. investigate frequency, type, fraction, and phenotypic consequences clinically relevant somatic single nucleotide (SNVs) characteristics corresponding genes, we retrospectively queried reported from a cohort ~ 12,000 samples submitted (ES) Baylor Genetics. We found 120 involving 107 including 80 SNVs in proband 40 parental/grandparental samples. Average alternate allele fraction (AAF) autosomes X-linked genes females was 18.2% compared 34.8% males. Of these variants, 74 (61.7%) were classified pathogenic or likely 46 (38.3%) uncertain significance. Mosaic occurred associated autosomal dominant (AD) AD/autosomal recessive (AR) (67/120, 55.8%), (33/120, 27.5%), AD/somatic (10/120, 8.3%), AR (8/120, 6.7%) inheritance. note, 1.7% (2/120) which events described. Nine had recurrent unrelated individuals accounted 18.3% (22/120) all this study. The group enriched mosaicism affecting Ras signaling pathway genes. In sum, an estimated 1.5% molecular diagnoses made could be attributed variant proband, while parental identified 0.3% families analyzed. As ES design favors breadth over depth coverage, estimate prevalence represents underestimate total number our cohort.

Language: Английский

---