Biology subjects

Woodbury-Smith, M.

Publications and source records attributed to Woodbury-Smith, M..

3 recordsLinked to original sources

bioRxiv2024

Horizon: CNV interpretation through rapid automated ACMG-aligned pathogenicity analysis

PurposeOur study assesses the Horizon model, a novel CNV classification tool developed in line with American College of Medical Genetics (ACMG) guidelines, to enhance the classification of pathogenicity in CNVs. MethodsHorizon utilizes a ranking-based algorithm, incorporating multiple proprietary databases and variant inheritance models as per ACMG standards. The models effectiveness was verified through Area Under the Curve (AUC) analyses on three datasets comprising 696 pathogenic inherited or de novo variants, as classified by clinical geneticists and several established tools. ResultsHorizon achieved an AUC of 0.97 in the discovery cohort, demonstrating high accuracy in CNV interpretation and proficiency in predicting pathogenicity. We observed an AUC of 0.87 in the de novo variant cohort and an overall AUC of 0.94 across all cohorts, surpassing tools like ClassifyCNV and AnnotSV. It showed particular effectiveness in interpreting duplication CNVs and the highest performance for CNVs sized 3-5 Mb. ConclusionThe Horizon model offers robust and accurate CNV interpretation, outperforming existing tools and aligning closely with clinical evaluations. Its comprehensive approach, integrating a range of genomic features and following ACMG guidelines, makes it a crucial tool in the genomic interpretation landscape, facilitating the rapid and accurate diagnosis of genetic disorders.

genomics↗

bioRxiv2023

Evolutionary constraint genes implicated in autism spectrum disorder across 2,054 nonhuman primate genomes

BackgroundSignificant progress has been made in elucidating the genetic underpinning of Autism Spectrum Disorder (ASD). This childhood-onset chronic disorder of cognition, communication and behaviour ranks among the most severe from a public health perspective, and it is therefore hoped that new discoveries will lead to better therapeutic options. However, there are still significant gaps in our understanding of the link between genomics, neurobiology and clinical phenotype in scientific discovery. New models are therefore needed to address these gaps. Rhesus macaques (Macaca mulatta) have been extensively used for preclinical neurobiological research because of remarkable similarities to humans across biology and behaviour that cannot be captured by other experimental animals. MethodsWe used the macaque Genotype and Phenotype (mGAP) resource (v2.0) consisting of 2,054 macaque genomes to examine patterns of evolutionary constraint in known human neurodevelopmental genes. Residual variation intolerance scores (RVIS) were calculated for all annotated autosomal genes (N = 18,168) and Gene Set Enrichment Analysis (GSEA) was used to examine patterns of constraint across ASD genes and related neurodevelopmental genes. ResultsWe demonstrated that patterns of constraint across autosomal genes are correlated in humans and macaques, and that ASD-implicated genes exhibit significant constraint in macaques (p = 9.4 x 10-27). Among macaques, many key ASD genes were observed to harbour predicted damaging mutations. A small number of key ASD genes that are highly intolerant to mutation in humans, however, showed no evidence of similar intolerance in macaques (CACNA1D, CNTNAP2, MBD5, AUTS2 and NRXN1). Constraint was also observed across genes implicated in intellectual disability (p = 1.1 x 10-46), epilepsy (p = 2.1 x 10-33) and schizophrenia (p = 4.2 x 10-45), and for an overlapping neurodevelopmental gene set (p = 4.0 x 10-10) LimitationsThe lack of behavioural phenotypes among the macaques whose genotypes were studied means that we are unable to further investigate whether genetic variants have similar phenotypic consequences among nonhuman primates. ConclusionThe presence of pathological mutations in ASD genes among macaques, and the evidence of similar constraints in these genes to humans, provide a strong rationale for further investigation of genotype-phenotype relationships in nonhuman primates. This highlights the importance of identifying phenotypic behaviours associated with clinical symptoms, elucidating the neurobiological underpinnings of ASD, and developing primate models for translational research to advance approaches for precision medicine and therapeutic interventions.

genetics↗

bioRxiv2021

Region-specific KCC2 rescue by rhIGF-1 and oxytocin in a mouse model of Rett syndrome

Rett syndrome (RTT) is characterized by dysfunction in neuronal excitation/inhibition (E/I) balance, potentially impacting seizure susceptibility via deficits in K+/Cl- cotransporter 2 (KCC2) function. Mice lacking the Methyl-CpG binding protein 2 (MeCP2) recapitulate many symptoms of RTT, and recombinant human insulin-like growth factor-1 (rhIGF-1) restores KCC2 expression and E/I balance in MeCP2 KO mice. However, clinical trial outcomes of rhIGF-1 in RTT have been variable, and increasing its therapeutic efficacy is highly desirable. To this end, the neuropeptide oxytocin (OXT) is promising, as it also critically modulates KCC2 function during early postnatal development. We measured basal KCC2 expression levels in MeCP2 KO mice and identified three key frontal brain regions showing KCC2 alterations in young adult mice but not in postnatal P10 animals. We thus hypothesized that deficits in an IGF-1/OXT signaling crosstalk modulating KCC2 may occur in RTT during postnatal development. Consistently, we detected alterations of IGF-1 receptor (IGF-1R) and OXT receptor (OXTR) levels in those brain areas. rhIGF-1 and OXT treatments in KO mice rescued KCC2 expression in a region-specific and complementary manner. These results suggest that region-selective combinatorial pharmacotherapeutic strategies could be the most effective at normalizing E/I balance in key brain regions subtending the RTT pathophysiology.

neuroscience↗