Biology subjects

Wakeling, M. N.

Publications and source records attributed to Wakeling, M. N..

3 recordsLinked to original sources

bioRxiv2020

Annotating high-impact 5'untranslated region variants with the UTRannotator

SummaryCurrent tools to annotate the predicted effect of genetic variants are heavily biased towards protein-coding sequence. Variants outside of these regions may have a large impact on protein expression and/or structure and can lead to disease, but this effect can be challenging to predict. Consequently, these variants are poorly annotated using standard tools. We have developed a plugin to the Ensembl Variant Effect Predictor, the UTRannotator, that annotates variants in 5untranslated regions (5UTR) that create or disrupt upstream open reading frames (uORFs). We investigate the utility of this tool using the ClinVar database, providing an annotation for 30.8% of all 5UTR (likely) pathogenic variants, and highlighting 31 variants of uncertain significance as candidates for further follow-up. We will continue to update the UTR annotator as we gain new knowledge on the impact of variants in UTRs. Availability and implementationUTRannotator is freely available on Github: https://github.com/ImperialCardioGenetics/UTRannotator Supplementary informationSupplementary data are available at bioRxiv.

bioinformatics↗

bioRxiv2019

SavvyCNV: genome-wide CNV calling from off-target reads

Identifying copy number variants (CNVS) can provide diagnoses to patients and provide important biological insights into human health and disease. Current exome and targeted sequencing approaches cannot detect clinically and biologically-relevant CNVs outside their target area. We present SavvyCNV, a tool which uses off-target read data to call CNVs genome-wide. Up to 70% of sequencing reads from exome and targeted sequencing fall outside the targeted regions - SavvyCNV exploits this free data.\n\nWe benchmarked SavvyCNV using truth sets generated from genome sequencing data and Multiplex Ligation-dependent Probe Amplification assays. SavvyCNV called CNVs with high precision and recall, outperforming five state-of-the-art CNV callers at calling CNVs genome-wide using off-target or on-target reads from targeted panel and exome sequencing. Furthermore SavvyCNV was able to call previously undetected clinically-relevant CNVs from targeted panel data highlighting the utility of this tool within the diagnostic setting. SavvyCNV is freely available.

bioinformatics↗

bioRxiv2018

Comprehensive screening shows that mutations in the known syndromic genes are rare in individuals presenting with hyperinsulinaemic hypoglycaemia

ObjectiveHyperinsulinaemic hypoglycaemia (HH) can occur in isolation or more rarely feature as part of a syndrome. Screening for mutations in the syndromic HH genes is guided by phenotype with genetic testing used to confirm the clinical diagnosis. As HH can be the presenting feature of a syndrome it is possible that mutations will be missed as these genes are not routinely screened in all newly diagnosed individuals. We investigated the frequency of pathogenic variants in syndromic genes in individuals with HH who had not been clinically diagnosed with a syndromic disorder at referral for genetic testing.\n\nDesignWe used genome sequencing data to assess the prevalence of mutations in syndromic HH genes in an international cohort of patients with HH of unknown genetic cause.\n\nMethodsWe undertook genome sequencing in 82 individuals with HH without a clinical diagnosis of a known syndrome at referral for genetic testing. Within this cohort we searched for the genetic aetiologies causing 20 different syndromes where HH had been reported as a feature.\n\nResultsWe identified a pathogenic KMT2D variant in a patient with HH diagnosed at birth, confirming a genetic diagnosis of Kabuki syndrome. Clinical data received following the identification of the mutation highlighted additional features consistent with the genetic diagnosis. Pathogenic variants were not identified in the remainder of the cohort.\n\nConclusionsPathogenic variants in the syndromic HH genes are rare but should be considered in newly diagnosed individuals as HH may be the presenting feature.

genetics↗