Featured
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Article
| Open Access
DeMAG predicts the effects of variants in clinically actionable genes by integrating structural and evolutionary epistatic features
Interpretation of rare genetic variants remains challenging. Here, the authors develop a supervised variant effect predictor for use in clinically actionable genes which incorporates evolutionary and structural relationships between residues and has balanced specificity and sensitivity.
- Federica Luppino
- , Ivan A. Adzhubei
- & Agnes Toth-Petroczy
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Article
| Open Access
Sequence terminus dependent PCR for site-specific mutation and modification detection
Rapid and facile detection of specific nucleic acid modifications could have numerous applications. Here the authors present Specific Terminal Mediated Polymerase Chain Reaction (STEM-PCR) as a generic and accessible approach, and demonstrate proof-of-principle cancer biomarker detection.
- Gaolian Xu
- , Hao Yang
- & Hongchen Gu
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Article
| Open Access
Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation
PREGCARE is a new strategy for families who had a child with a pathogenic de novo mutation, that efficiently identifies couples at higher recurrence risk due to parental mosaicism, while reassuring many others that their recurrence risk is negligible.
- Marie Bernkopf
- , Ummi B. Abdullah
- & Anne Goriely
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Article
| Open Access
Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing
Whole genome sequencing is emerging as a first-line test for rare genetic diseases. In this study, authors maximise diagnoses by supplementing existing semiautomated analyses with clinically driven reevaluation of genomic data by a specialist multidisciplinary team.
- William L. Macken
- , Micol Falabella
- & Robert D. S. Pitceathly
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Article
| Open Access
Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes
Accurate classification of genetic variants is critical for research and patient care. Here, the authors report that population-based associations between rare variants and quantitative endophenotypes for monogenic diseases can provide support for variant pathogenicity.
- Jennifer L. Halford
- , Valerie N. Morrill
- & Steven A. Lubitz
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Article
| Open Access
An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases
Rapid diagnosis and implementation of treatments is crucial in many genetic conditions. Here the authors describe Genome-to-Treatment, a virtual disease management system that can achieve a rapid diagnosis by expedited whole genome sequencing in 13.5 hours and provide guidance to clinicians for possible therapies.
- Mallory J. Owen
- , Sebastien Lefebvre
- & Stephen F. Kingsmore
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Article
| Open Access
The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism
Albinism is a rare disorder often caused by high-effect rare variants in the TYR gene. Here, the authors study a large albinism cohort and find that a common variant in the TYR promoter contributes to albinism by modifying the penetrance of other common variants, demonstrating a complex genetic architecture.
- Vincent Michaud
- , Eulalie Lasseaux
- & Panagiotis I. Sergouniotis
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Article
| Open Access
Ultrasensitive and visual detection of SARS-CoV-2 using all-in-one dual CRISPR-Cas12a assay
Rapid and early detection of SARS-CoV-2 will aid intervention to stop disease spread. Here the authors present a one-pot CRISPR-based rapid detection system with visual readout.
- Xiong Ding
- , Kun Yin
- & Changchun Liu
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Article
| Open Access
A universal and independent synthetic DNA ladder for the quantitative measurement of genomic features
Standard units of measurement are required for a quantitative description of the genome. Here, the authors present a universal synthetic DNA ladder that can measure genetic abundance in next-generation sequencing libraries.
- Andre L. M. Reis
- , Ira W. Deveson
- & Tim R. Mercer
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Article
| Open Access
Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data
Systematic analysis of postzygotic mosaicism (PZM) is difficult due to challenges in detecting such events. Here, Wright et al. analyse trio exome sequencing data from blood and saliva of 4,293 probands with developmental disorders from the DDD Study and estimate that >3% of causative de novo mutations result from PZM.
- C. F. Wright
- , E. Prigmore
- & M. E. Hurles
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Article
| Open Access
Improving the diagnostic yield of exome- sequencing by predicting gene–phenotype associations using large-scale gene expression analysis
A genetic diagnosis remains unattainable for many individuals with a rare disease because of incomplete knowledge about the genetic basis of many diseases. Here, the authors present the web-based tool GADO (GeneNetwork Assisted Diagnostic Optimization) that uses public RNA-seq data for prioritization of candidate genes.
- Patrick Deelen
- , Sipko van Dam
- & Lude Franke
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Article
| Open Access
Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP
Diagnostic filtering is an important step to analyze the functional and clinical significance of the large number of genetic variants identified from next-generation genome sequencing data. Here, the authors develop a flexible and scalable system for diagnostic filtering of genetic variants using G2P with Ensembl VEP.
- Anja Thormann
- , Mihail Halachev
- & David R. FitzPatrick
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Article
| Open Access
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls
Association between variants in 11 different genes and breast cancer risk has been established and sequencing of these genes is recommended to provide personalized diagnosis, therapy, and surveillance for the high-risk patients and their relatives. Here the authors analyse the frequency of germline pathogenic mutations in these genes specifically in a Japanese population.
- Yukihide Momozawa
- , Yusuke Iwasaki
- & Michiaki Kubo
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Article
| Open Access
Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance
Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.
- Kashyap A. Patel
- , Jarno Kettunen
- & Michael N. Weedon
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Article
| Open Access
Genetic diagnosis of Mendelian disorders via RNA sequencing
Genome sequencing alone fails to provide a genetic diagnosis for many Mendelian disorder patients. Here, the authors utilize RNA sequencing to complement genotyping of patients with a rare mitochondrial disease by detecting aberrant RNA expression, splicing and allele-specific expression.
- Laura S. Kremer
- , Daniel M. Bader
- & Holger Prokisch
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Muscle stem cells contribute to myofibres in sedentary adult mice
Skeletal muscle satellite cells are muscle stem cells believed to contribute only to regenerating myofibres. Here Keefe et al. show that in adult sedentary mice satellite cells continue to fuse with uninjured myofibres, but they are not globally required for the maintenance of aging muscles.
- Alexandra C. Keefe
- , Jennifer A. Lawson
- & Gabrielle Kardon
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Article
| Open Access
An analytical framework for optimizing variant discovery from personal genomes
The standardization of clinical sequencing data generation and analysis is of critical importance. Here, the authors develop the Genome Comparison and Analytic Testing platform to facilitate the development of performance metrics and comparisons of analysis tools for clinical sequencing studies.
- Gareth Highnam
- , Jason J. Wang
- & David Mittelman
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Article
| Open Access
Escape from crossover interference increases with maternal age
Recombination is a meiotic process that ensures accurate chromosome segregation. Here, the authors characterize recombination patterns in over 4,200 families. Their results show that recombination rate increases with maternal age, and highlight sex differences in the distribution of these events.
- Christopher L. Campbell
- , Nicholas A. Furlotte
- & Adam Auton
Ultrasensitive single-step CRISPR detection of monkeypox virus in minutes with a vest-pocket diagnostic device