Mendelian Gene Discovery: Fast and Furious with No End in Sight.

Gene discovery for Mendelian conditions (MCs) offers a direct path to understanding genome function. Approaches based on next-generation sequencing applied at scale have dramatically accelerated gene discovery and transformed genetic medicine. Finding the genetic basis of ∼6,000-13,000 MCs yet to be delineated will require both technical and computational innovation, but will rely to a larger extent on meaningful data sharing.

• Publication year

  2019

• Venue

  American Journal of Human Genetics

• Publication date

  2019-09-01

• Fields of study

  Biology, Medicine, Computer Science

• Identifiers
  DOI 10.1016/j.ajhg.2019.07.011PMID 31491408PMCID PMC6731362
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Identification of common genetic risk variants for autism spectrum disorder

  2019cited by this paper
• GGC Repeat Expansion and Exon 1 Methylation of XYLT1 Is a Common Pathogenic Variant in Baratela-Scott Syndrome.

  2019cited by this paper
• Integrating Genomics into Healthcare: A Global Responsibility.

  2019cited by this paper
• Insights into genetics, human biology and disease gleaned from family based genomic studies

  2019cited by this paper
• Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

  2019cited by this paper
• The Role of De Novo Noncoding Regulatory Mutations in Neurodevelopmental Disorders.

  2019cited by this paper
• Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes

  2019cited by this paper
• Mouse Genome Database (MGD) 2019

  2018cited by this paper
• Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles.

  2018cited by this paper
• De novo mutations in regulatory elements in neurodevelopmental disorders

  2018cited by this paper
• The unsolved rare genetic disease atlas? An analysis of the unexplained phenotypic descriptions in OMIM®

  2018cited by this paper
• OUTRIDER: A statistical method for detecting aberrantly expressed genes in RNA sequencing data

  2018cited by this paper
• A Multiplex Homology-Directed DNA Repair Assay Reveals the Impact of More Than 1,000 BRCA1 Missense Substitution Variants on Protein Function.

  2018cited by this paper
• Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

  2017cited by this paper
• Matchmaker Exchange

  2017cited by this paper
• A map of constrained coding regions in the human genome

  2017influential reference
• Duplicated Enhancer Region Increases Expression of CTSB and Segregates with Keratolytic Winter Erythema in South African and Norwegian Families.

  2017cited by this paper
• A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease.

  2016cited by this paper
• Whole Genome Sequencing Identifies a 78 kb Insertion from Chromosome 8 as the Cause of Charcot-Marie-Tooth Neuropathy CMTX3

  2016cited by this paper
• The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.

  2015cited by this paper
• TBX6 null variants and a common hypomorphic allele in congenital scoliosis.

  2015cited by this paper
• The Matchmaker Exchange: A Platform for Rare Disease Gene Discovery

  2015influential reference
• Participant‐Driven Matchmaking in the Genomic Era

  2015cited by this paper
• Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.

  2014cited by this paper
• Pediatric Data Sharing in Genomic Research: Attitudes and Preferences of Parents

  2014cited by this paper
• The shifting model in clinical diagnostics: how next-generation sequencing and families are altering the way rare diseases are discovered, studied, and treated

  2014cited by this paper
• Large-scale discovery of novel genetic causes of developmental disorders

  2014cited by this paper
• Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus.

  2012cited by this paper
• Inheritance of low-frequency regulatory SNPs and a rare null mutation in exon-junction complex subunit RBM8A causes TAR

  2012cited by this paper
• A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.

  2011cited by this paper
• A de novo paradigm for mental retardation

  2010cited by this paper
• Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome

  2010cited by this paper
• Exome sequencing identifies the cause of a Mendelian disorder

  2009cited by this paper
• Targeted Capture and Massively Parallel Sequencing of Twelve Human Exomes

  2009cited by this paper
• Mendelian disorders deserve more attention

  2006cited by this paper
• Positional cloning moves from perditional to traditional

  1995cited by this paper

• Impact of Laboratory-Driven Proactive Reanalysis: Reclassification to Positive in 5% of Initially Negative or Uncertain Exome Sequencing Cases.

  2025cites this paper
• A scalable approach for genomic-first rare disorder detection in a healthcare-based population.

  2025cites this paper
• High-throughput behavioural phenotyping of 25 C. elegans disease models including patient-specific mutations

  2025cites this paper
• Inequalities and Inclusion in Genomics Applied to Healthcare: A Latin American Perspective.

  2025cites this paper
• Translating the Power of Precision Medicine Into the World of Communication Disorders

  2025cites this paper
• Lipid transport is necessary for neocortical lamination

  2025cites this paper
• AI-Based Facial Phenotyping Supports a Shared Molecular Axis in PACS1-, PACS2-, and WDR37-Related Syndromes

  2025cites this paper
• Diagnosis of Australasian Patients with Neuromuscular Disease: Insights from a Comprehensive Panel Approach.

  2025cites this paper
• MorPhiC Consortium: towards functional characterization of all human genes

  2025cites this paper
• The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the clinical validity of 111 gene-disease relationships

  2025cites this paper
• MENDELSEEK: An algorithm that predicts Mendelian Genes and elucidates what makes them special

  2025cites this paper
• Poorly described phenotypes add to the misfortune of rare diseases.

  2025cites this paper
• Bi-allelic variants in BRF2 are associated with perinatal death and craniofacial anomalies

  2025cites this paper
• Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database

  2025cites this paper
• GREGoR: accelerating genomics for rare diseases

  2025cites this paper
• Large Class of Neurodevelopmental Disorders Requires Genome Sequencing for Diagnosis

  2025cites this paper
• Global partnerships in rare disease research

  2025cites this paper
• The biology of congenital urinary bladder outflow obstruction.

  2025cites this paper
• Perspectives on the Current and Future State of Artificial Intelligence in Medical Genetics

  2025cites this paper
• Combined genomics and proteomics unveils elusive variants and vast aetiologic heterogeneity in dystonia

  2025cites this paper
• Proteome-wide assessment of differential missense variant clustering in neurodevelopmental disorders and cancer

  2025cites this paper
• The RDI-Lancet Commission on Rare Diseases: improving visibility to address health-care disparities for 400 million people.

  2025cites this paper
• Overcoming Barriers to Genomic Medicine Implementation.

  2025cites this paper
• Ribonucleases in Mendelian disease: Characterization and insight from model organisms

  2025cites this paper
• Artificial intelligence in clinical genetics

  2025cites this paper
• Familial severe skeletal Class II malocclusion with gingival hyperplasia caused by a complex structural rearrangement at the KCNJ2-KCNJ16 locus

  2024cites this paper
• Exploiting fly models to investigate rare human neurological disorders

  2024cites this paper
• Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone

  2024cites this paper
• Modelling human genetic disorders in Xenopus tropicalis

  2024cites this paper
• Genetics of inherited peripheral neuropathies and the next frontier: looking backwards to progress forwards

  2024cites this paper
• Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database

  2024cites this paper
• Long-Read DNA and RNA Sequencing to Streamline Clinical Genetic Testing and Reduce Barriers to Comprehensive Genetic Testing.

  2024cites this paper
• Next-generation sequencing analysis with a population-specific reference genome

  2024cites this paper
• Clinical, neuroimaging and genetic findings in Brazilian patients with neurodegeneration with brain iron accumulation.

  2024cites this paper
• GPAD: a natural language processing-based application to extract the gene-disease association discovery information from OMIM

  2024influential citation
• Next-generation sequencing analysis with a population-specific human reference genome.

  2024cites this paper
• The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the Clinical Validity of 111 Gene-Disease Relationships

  2024cites this paper
• The clinical application and laboratory management of molecular genetic diagnosis in children's hospital

  2024cites this paper
• The WHO genomics program of work for equitable implementation of human genomics for global health

  2024cites this paper
• NeuroTri2-VISDOT: An open-access tool to harness the power of second trimester human single cell data to inform models of Mendelian neurodevelopmental disorders

  2024cites this paper
• Narrowing the Diagnostic Gap: Genomes, Episignatures, Long-Read Sequencing and Health Economic Analyses in an Exome-Negative Intellectual Disability Cohort.

  2024cites this paper
• Considerations for reporting variants in novel candidate genes identified during clinical genomic testing

  2024cites this paper
• High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia

  2024cites this paper
• Implementing genomic medicine in clinical practice for adults with undiagnosed rare diseases

  2024cites this paper
• The expanding diagnostic toolbox for rare genetic diseases

  2024cites this paper
• Whole genome sequencing in clinical practice

  2024cites this paper
• Functional categorization of gene regulatory variants that cause Mendelian conditions

  2024cites this paper
• A guide to gene–disease relationships in nephrology

  2024cites this paper
• Improving access to exome sequencing in a medically underserved population through the Texome Project.

  2024cites this paper
• Whole genome sequencing as a first‐tier diagnostic test for infants in neonatal intensive care units: A pilot study in Brazil

  2024cites this paper
• GREGoR: Accelerating Genomics for Rare Diseases

  2024cites this paper
• Long-read genome sequencing and variant reanalysis increase diagnostic yield in neurodevelopmental disorders

  2024cites this paper
• Long-read genome sequencing and variant reanalysis increase diagnostic yield in neurodevelopmental disorders

  2024cites this paper
• Discovery of novel genetic syndromes in Latin America: Opportunities and challenges

  2024cites this paper
• VUS next in rare diseases? Deciphering genetic determinants of biomolecular condensation

  2024cites this paper
• VARista: a free web platform for streamlined whole-genome variant analysis across T2T, hg38, and hg19

  2024cites this paper
• The book is just being written: The enduring journey of parents of children with emerging‐ ultrarare disorders

  2024cites this paper
• Consensus reporting guidelines to address gaps in descriptions of ultra-rare genetic conditions

  2024cites this paper
• Lethal phenotypes in Mendelian disorders.

  2024cites this paper
• The landscape of regional missense mutational intolerance quantified from 125,748 exomes

  2024cites this paper
• AI-MARRVEL - A Knowledge-Driven AI System for Diagnosing Mendelian Disorders.

  2024cites this paper
• Exome sequencing reveals genetic heterogeneity and clinically actionable findings in children with cerebral palsy

  2024cites this paper
• Federated analysis of autosomal recessive coding variants in 29,745 developmental disorder patients from diverse populations

  2024cites this paper
• IRF2BPL‐Related Disorder, Causing Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and Seizures (NEDAMSS) Is Characterized by Pathology Consistent with DRPLA

  2024cites this paper
• One-Sided Matching Portal (OSMP): A Tool to Facilitate Rare Disease Patient Matchmaking

  2024cites this paper
• Using multi-scale genomics to associate poorly annotated genes with rare diseases

  2024influential citation
• Leaving no patient behind! Expert recommendation in the use of innovative technologies for diagnosing rare diseases

  2024cites this paper
• Equity in action: The Diagnostic Working Group of The Undiagnosed Diseases Network International

  2024cites this paper
• Considerations for reporting variants in novel candidate genes identified during clinical genomic testing.

  2024cites this paper
• SeqFirst: Building equity access to a precise genetic diagnosis in critically ill newborns

  2024cites this paper
• Clinical Advancement Forecasting

  2024cites this paper
• How do stochastic processes and genetic threshold effects explain incomplete penetrance and inform causal disease mechanisms?

  2024cites this paper
• Lethal phenotypes in Mendelian disorders

  2024cites this paper
• Variant functional assessment in Drosophila by overexpression: what can we learn?

  2024cites this paper
• Next-generation sequencing and bioinformatics in rare movement disorders

  2024cites this paper
• Redefining cerebral palsies as a diverse group of neurodevelopmental disorders with genetic aetiology

  2023cites this paper
• FiTMuSiC: leveraging structural and (co)evolutionary data for protein fitness prediction

  2023cites this paper
• Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans

  2023cites this paper
• Genomic newborn screening for rare diseases

  2023cites this paper
• High-Content Small Molecule Screen Identifies a Novel Compound That Restores AP-4-Dependent Protein Trafficking in Neuronal Models of AP-4-Associated Hereditary Spastic Paraplegia

  2023cites this paper
• Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

  2023cites this paper
• A brief review on the history of classic genetics

  2023cites this paper
• Exome and genome sequencing for rare genetic disease diagnosis: A scoping review and critical appraisal of clinical guidance documents produced by genetics professional organizations.

  2023cites this paper
• The future of commercial genetic testing

  2023cites this paper
• Annual Review of Genomics and Human Genetics: DECIPHER: Improving Genetic Diagnosis Through Dynamic Integration of Genomic and Clinical Data

  2023cites this paper
• Epilepsy panels in clinical practice: Yield, variants of uncertain significance, and treatment implications.

  2023cites this paper
• Biallelic variants in NSUN6 cause an autosomal recessive neurodevelopmental disorder.

  2023cites this paper
• Federated analysis of the contribution of recessive coding variants to 29,745 developmental disorder patients from diverse populations

  2023cites this paper
• Advancing Understanding of Inequities in Rare Disease Genomics

  2023influential citation
• Rare genetic disorders: Beyond whole‐exome sequencing

  2023cites this paper
• A retrospective analysis of phosphatase catalytic subunit gene variants in patients with rare disorders identifies novel candidate neurodevelopmental disease genes

  2023cites this paper
• Automated prioritization of sick newborns for whole genome sequencing using clinical natural language processing and machine learning

  2023cites this paper
• Reactive gene curation to support interpretation and reporting of a clinical genome test for rare disease: Experience from over 1,000 cases

  2023cites this paper
• OutSingle: a novel method of detecting and injecting outliers in RNA-Seq count data using the optimal hard threshold for singular values

  2023cites this paper
• Clinical Validation of Tagmentation-Based Genome Sequencing for Germline Disorders.

  2023cites this paper
• A review of genotrichoses and hair pathology associated with inherited skin diseases.

  2023cites this paper
• Exome/Genome Sequencing in Undiagnosed Syndromes

  2023cites this paper
• Systematic analysis of variants escaping nonsense-mediated decay uncovers candidate Mendelian diseases.

  2023cites this paper
• Association between de novo variants of nuclear-encoded mitochondrial-related genes and undiagnosed developmental disorder and autism

  2023cites this paper
• Will variants of uncertain significance still exist in 2030?

  2023cites this paper