Targeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project

Editorial Material Biochemistry & Molecular Biology

Time to make rare disease diagnosis accessible to all

Heidi L. Rehm

Summary: Studies have shown that genomic analysis is valuable for diagnosing rare diseases, but access to it is still limited. Global data sharing is necessary to further enhance our understanding of all causes of rare diseases.

NATURE MEDICINE (2022)

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Article Genetics & Heredity

A gene-to-patient approach uplifts novel disease gene discovery and identifies 18 putative novel disease genes

Eleanor G. Seaby et al.

Summary: This study identified predicted haploinsufficient disease genes using a metric of intolerance to gene inactivation, matching de novo loss-of-function variants in constrained genes to rare disease patients. By reducing excess analytical noise through large-scale data aggregation, novel disease gene discoveries were accelerated with 61% being independently published within two years.

GENETICS IN MEDICINE (2022)

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Article Multidisciplinary Sciences

A joint NCBI and EMBL-EBI transcript set for clinical genomics and research

Joannella Morales et al.

Summary: Comprehensive genome annotation is crucial for understanding clinically relevant variants, but the lack of standardized reporting and browser display complicates interpretation and reporting. To address this, Ensembl/GENCODE and RefSeq launched the MATCHED Annotation from NCBI and EMBL-EBI (MANE) collaboration to define universal standards for variant reporting and browser display. The MANE transcript sets provide representative transcripts for each human protein-coding gene, improving consistency and facilitating clinical interpretation.

NATURE (2022)

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Review Genetics & Heredity

Best practices for the interpretation and reporting of clinical whole genome sequencing

Christina A. Austin-Tse et al.

Summary: Whole genome sequencing (WGS) has the potential to become a first-tier diagnostic test for patients with rare genetic disorders. However, there is a lack of standards for defining and implementing the best test. To address this issue, the Medical Genome Initiative formed a consortium of experts to publish best practice recommendations and improve the quality of clinical WGS.

NPJ GENOMIC MEDICINE (2022)

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Article Medicine, General & Internal

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report

Damian Smedley et al.

Summary: The pilot study, involving 4660 participants with rare diseases, provided actionable diagnoses and identified three newly implicated disease genes, offering a road map for the larger implementation of genome sequencing in the setting of a national health service.

NEW ENGLAND JOURNAL OF MEDICINE (2021)

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Article Genetics & Heredity

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

David T. Miller et al.

GENETICS IN MEDICINE (2021)

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Correction Multidisciplinary Sciences

The mutational constraint spectrum quantified from variation in 141,456 humans (vol 581, pg 434, 2020)

Sanna Gudmundsson et al.

NATURE (2021)

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Review Genetics & Heredity

Strategies to Uplift Novel Mendelian Gene Discovery for Improved Clinical Outcomes

Eleanor G. Seaby et al.

Summary: This article explores strategies to identify novel Mendelian genes and their impact on clinical care and therapeutics. It discusses the importance of data sharing, phenotype-driven approaches, patient-led approaches, large-scale genomic sequencing projects, constraint-based methods, integration of multi-omics data, and gene-to-patient methods. The health economic advantages of novel gene discovery and potential future methods for improved clinical outcomes are also considered.

FRONTIERS IN GENETICS (2021)

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Review Biotechnology & Applied Microbiology