Genomics and Rare Diseases

Variant landscape of the RYR1 gene based on whole genome sequencing of the Singaporean population

The paper describes the RYR1 variant landscape in a Singapore cohort using whole genome sequencing, identifying pathogenic variants and their allele frequencies across ethnic groups.

Whole genome sequencing as an investigational device for return of hereditary disease risk and pharmacogenomic results as part of the All of Us Research Program

The paper describes the process of obtaining an FDA IDE for returning genomic results via WGS in the All of Us Research Program and presents validation results.

Machine-learning algorithm for identifying and predicting amyotrophic lateral sclerosis causal mutations

The paper develops a machine learning classifier to distinguish ALS-causative from non-ALS-causative variants with high accuracy using nine key mutation assessors.

Inherited variants in CHD3 demonstrate variable expressivity in Snijders Blok-Campeau syndrome

The paper shows inherited CHD3 variants cause Snijders Blok-Campeau syndrome with variable expressivity, overlapping with de novo variants' phenotypes, and suggests reduced penetrance is not due to expression compensation.

CNV-ClinViewer: Enhancing the clinical interpretation of large copy-number variants online

CNV-ClinViewer provides a web tool for clinical interpretation of large copy-number variants by integrating patient and population data with biomedical annotations.

Functional analysis of a novel de novo variant in PPP5C associated with microcephaly, seizures, and developmental delay

The paper functionally validates a de novo PPP5C variant in a human proband using C. elegans, showing it causes loss-of-function and is likely responsible for the patient's phenotypes.

Medical Evaluation of Unanticipated Monogenic Disease Risks Identified through Newborn Genomic Screening: Findings from the BabySeq Project

The paper evaluates unanticipated monogenic disease risks found in newborns through genomic screening, finding most risks are actionable and lead to medical interventions.

Genome Alert!: a standardized procedure for genomic variant reinterpretation and automated genotype-phenotype reassessment in clinical routine

Genome Alert! automatically detects changes in variant classifications and gene-disease associations over time, improving clinical interpretation of genomic data with minimal human effort.

A general framework for identifying rare variant combinations in complex disorders

This paper introduces a framework to identify rare variant combinations in complex disorders by combining the apriori algorithm with statistical inference, revealing significant associations with phenotypes like ID and schizophrenia.

Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes

The paper presents diagnostic analyses of 960 pediatric rare disease families using genomic sequencing and machine learning, finding higher diagnostic rates with long-read sequencing and highlighting challenges in variant interpretation.

Contiguously-hydrophobic sequences are functionally significant throughout the human exome

The paper examines the relationship between contiguous hydrophobic sequences and functional impact of SNPs, finding strong correlations with disease association and selective constraint.

The Regulatory Mendelian Mutation score for GRCh38

The paper updates the Regulatory Mendelian Mutation score for GRCh38 and provides a website and API for variant scoring.

seqr: a web-based analysis and collaboration tool for rare disease genomics

seqr is a web-based tool for analyzing rare disease genomic data, enabling variant filtering, annotation, and collaboration, with over 10,000 families analyzed and 300 novel disease genes discovered.

Variomes: a high recall search engine to support the curation of genomic variants

Variomes is a system that curates genomic variants by searching literature and prioritizing clinically actionable variants based on publication volume.

Middle Eastern Genetic Variation Improves Clinical Annotation of the Human Genome

The paper highlights the importance of Middle Eastern genetic variation in improving clinical genome annotation and variant interpretation by presenting a new database with unique variants not found in existing resources.

Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1/GAT-1 variants

The paper investigates the functional consequences of SLC6A1 variants, finding haploinsufficiency underlies neurodevelopmental phenotypes and identifying missense residues sensitive to substitution.

Performance Comparison of Computational Prediction Methods for the Function and Pathogenicity of Non-coding Variants

The paper evaluates 24 computational methods for predicting non-coding variant function and pathogenicity across four benchmark datasets, finding varying performance across different variant types.

Missense variants reveal functional insights into the human ARID family of gene regulators

The paper uses missense variant depletion patterns to identify functional sites in ARID family proteins and reveals sub-functionalization through domain-level comparisons.

TADA - a Machine Learning Tool for Functional Annotation based Prioritisation of Putative Pathogenic CNVs

TADA prioritizes pathogenic CNVs using functional annotations and machine learning, achieving high AUC scores for deletions and duplications.

Mitochondrial DNA variation across 56,434 individuals in gnomAD

The paper presents a pipeline to call mitochondrial DNA variants in gnomAD, reporting population frequencies for 10,850 unique mtDNA variants across 56,434 individuals.

Discovery of an unusual high number of de novo mutations in sperm of older men using duplex sequencing

The paper uses duplex sequencing to analyze de novo mutations in sperm DNA from older and younger donors, finding higher mutation frequencies and recurrence in older donors.

ModelMatcher: A scientist-centric online platform to facilitate collaborations between stakeholders of rare and undiagnosed disease research

ModelMatcher connects researchers, clinicians, and stakeholders in rare disease research to accelerate translational studies and collaborations.

Clinical prediction of pathogenic variants in non-coding regions of the human genome.

PANCO reclassifies variants of uncertain significance in non-coding regions with high accuracy using integrated functional and evolutionary data.

Characterization of Arabian Peninsula whole exomes: exploring high inbreeding features

The paper characterizes Arabian Peninsula whole exomes, identifying high inbreeding features and a high burden of potentially deleterious variants.

Vasor: Accurate prediction of variant effects for amino acid substitutions in MDR3

Vasor is a machine learning model that accurately predicts the pathogenicity of MDR3 missense variants, outperforming existing tools and providing a webserver for predictions.

GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation

GeneTerpret streamlines genomic variant interpretation by integrating multiple data sources and ACMG criteria to prioritize potentially causal variants for a given genome and phenotype.

Genetic constraint at single amino acid resolution improves missense variant prioritisation and gene discovery

This paper introduces HMC, a high-resolution genetic constraint score for missense variants, improving variant prioritization and gene discovery for developmental disorders.

GREEN-DB: A framework for the annotation and prioritization of non-coding regulatory variants from whole-genome sequencing data

GREEN-DB annotates and prioritizes non-coding regulatory variants from whole-genome sequencing data by integrating regulatory annotations, constraint metrics, and variant impact scores.

GestaltMatcher: Overcoming the limits of rare disease matching using facial phenotypic descriptors

GestaltMatcher improves diagnosis of ultra-rare genetic disorders by matching facial phenotypes to molecular diagnoses using a deep learning model trained on a large dataset of patient photographs.

Centers for Mendelian Genomics: A decade of facilitating gene discovery

The paper describes the role of the Centers for Mendelian Genomics in advancing gene discovery through data sharing, collaboration, and resource development over the past decade.