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Exome sequencing of 2,871 probands with congenital heart disease (CHD) provides new insights into the genetic architecture of these disorders. The results implicate new genes in CHD pathogenesis and highlight striking overlap between genes with damaging de novo mutations in individuals with CHD and autism. Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent–offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

Although their intention was to create a model of meningioma, investigators instead observed the development of cerebral cavernous malformations in their engineered mice, prompting them to test the implicated genes in patients with these malformations.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent–offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two ( TUBA1A and CTNNB1 ) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB , and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy. Whole-exome sequencing of 250 parent–offspring trios identifies an enrichment of rare damaging de novo mutations in individuals with cerebral palsy and implicates genetically mediated dysregulation of early neuronal connectivity in the etiology of this disorder.

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. The largest whole-exome sequencing study of sporadic congenital hydrocephalus identities mutations associated with disrupted fetal neuro-gliogenesis as the primary pathophysiological event in a significant number of cases.

INTRODUCTION Congenital Hydrocephalus (CH) affects 1/1,000 live births and costs the US healthcare system over $2 billion annually. Surgical cerebrospinal fluid diversion exhibits high failure rates and substantial morbidity. Limited understanding of pathogenesis warrants identification of crucial genetic drivers underlying CH and their impact on brain development. METHODS Exome analysis of 381 radiographically-confirmed, neurosurgically-treated sporadic CH probands (including 232 case-parent trios) identified genes with rare de novo or transmitted mutations conferring disease risk. Transcriptome analyses identified mid-gestational brain modules and cell-types enriched for cohort-determined CH risk genes, known genes previously implicated in isolated and syndromic forms of CH, and risk genes of Autism Spectrum Disorder (ASD) and Developmental Disorder (DD). RESULTS Exome analysis reveals 9 high confidence genes and 55 probable risk genes harboring CH-linked mutations. Together, cohort-determined and known CH genes enrich in a single network (“yellow” module) associated with ASD and DD. Functional profiling of the yellow module yields terms of cell and neuronal differentiation, congenital anomalies of craniofacial development, and behavioral abnormalities. Cohort-determined and known CH genes together enrich in nascent migrating excitatory neurons and cycling mitotic progenitors, occupying earlier stages of differentiation than ASD- and DD-enriched cell-types. CONCLUSION Genetic drivers of CH converge in a neurodevelopmental network and in early neurogenic cell-types, implicating genetic disruption of early brain development as a primary patho-mechanism for a significant subset of CH patients. Transcriptional overlap with ASD and DD may explain persistence of these conditions in CH patients despite surgical intervention, while greater potency of CH-enriched neural precursors may account for increased frequency of structural brain abnormalities in CH than in ASD or DD alone.

A Correction to this paper has been published: https://doi.org/10.1038/s41588-021-00780-8.

Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2′- O -Methyl (2′-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2′-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types. Short interfering siRNAs—siRNAs—have therapeutic potential in the treatment of disease; however, their delivery to target tissues is difficult. Here, Wu et al . chemically modify siRNAs and show that this improves loading into the siRNA silencing machinery and thus efficacy in eliminating cancer cells in mice.

Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2’-O-Methyl (2’-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2’-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM Domain Containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumors following MePS2-modified siRNA treatment, leading to a synergistic anti-tumor effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.