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.

[1]  K. Boycott,et al.  The unsolved rare genetic disease atlas? An analysis of the unexplained phenotypic descriptions in OMIM® , 2018, American journal of medical genetics. Part C, Seminars in medical genetics.

[2]  Orion J. Buske,et al.  The Matchmaker Exchange: A Platform for Rare Disease Gene Discovery , 2015, Human mutation.

[3]  Brent S. Pedersen,et al.  A map of constrained coding regions in the human genome , 2017, Nature Genetics.

[4]  P. Shannon,et al.  Exome sequencing identifies the cause of a Mendelian disorder , 2009, Nature Genetics.

[5]  Christian Gilissen,et al.  A de novo paradigm for mental retardation , 2010, Nature Genetics.

[6]  Stylianos E. Antonarakis,et al.  Mendelian disorders deserve more attention , 2006, Nature Reviews Genetics.

[7]  Justyna A. Karolak,et al.  Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway. , 2019, American journal of human genetics.

[8]  Emily H Turner,et al.  Targeted Capture and Massively Parallel Sequencing of Twelve Human Exomes , 2009, Nature.

[9]  Francis S. Collins,et al.  Positional cloning moves from perditional to traditional , 1995, Nature Genetics.

[10]  Matthew Might,et al.  Participant‐Driven Matchmaking in the Genomic Era , 2015, Human mutation.

[11]  Caroline F. Wright,et al.  De novo mutations in regulatory elements in neurodevelopmental disorders , 2018, Nature.

[12]  Matthias Griese,et al.  A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. , 2011, The New England journal of medicine.

[13]  E. Eichler,et al.  The Role of De Novo Noncoding Regulatory Mutations in Neurodevelopmental Disorders , 2019, Trends in Neurosciences.

[14]  Martin Kircher,et al.  GGC Repeat Expansion and Exon 1 Methylation of XYLT1 Is a Common Pathogenic Variant in Baratela-Scott Syndrome. , 2019, American journal of human genetics.

[15]  Matthew Might,et al.  The shifting model in clinical diagnostics: how next-generation sequencing and families are altering the way rare diseases are discovered, studied, and treated , 2014, Genetics in Medicine.

[16]  P. Robinson,et al.  Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus. , 2012, American journal of human genetics.

[17]  M. Waldenberger,et al.  Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome. , 2014, American journal of human genetics.

[18]  Ana Cvejic,et al.  Inheritance of low-frequency regulatory SNPs and a rare null mutation in exon-junction complex subunit RBM8A causes TAR , 2012, Nature Genetics.

[19]  Judith A. Blake,et al.  Mouse Genome Database (MGD) 2019 , 2018, Nucleic Acids Res..

[20]  J. Lupski,et al.  TBX6 null variants and a common hypomorphic allele in congenital scoliosis. , 2015, The New England journal of medicine.

[21]  Tomas W. Fitzgerald,et al.  Large-scale discovery of novel genetic causes of developmental disorders , 2014, Nature.

[22]  Giorgio Valentini,et al.  A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease. , 2016, American journal of human genetics.

[23]  John P. Rice,et al.  Identification of common genetic risk variants for autism spectrum disorder , 2019, Nature Genetics.

[24]  S. Zuchner,et al.  Whole Genome Sequencing Identifies a 78 kb Insertion from Chromosome 8 as the Cause of Charcot-Marie-Tooth Neuropathy CMTX3 , 2016, PLoS genetics.

[25]  Julien Gagneur,et al.  OUTRIDER: A Statistical Method for Detecting Aberrantly Expressed Genes in RNA Sequencing Data. , 2018, American journal of human genetics.

[26]  M. Gerstein,et al.  Insights into genetics, human biology and disease gleaned from family based genomic studies , 2019, Genetics in Medicine.

[27]  S. Hilsenbeck,et al.  Pediatric Data Sharing in Genomic Research: Attitudes and Preferences of Parents , 2014, Pediatrics.

[28]  Yufeng Shen,et al.  Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands , 2017, Nature Genetics.

[29]  Emily H Turner,et al.  Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome , 2010, Nature Genetics.

[30]  Tomasz Stokowy,et al.  Duplicated Enhancer Region Increases Expression of CTSB and Segregates with Keratolytic Winter Erythema in South African and Norwegian Families. , 2017, American journal of human genetics.

[31]  Jeffrey Braithwaite,et al.  Integrating Genomics into Healthcare: A Global Responsibility. , 2019, American journal of human genetics.

[32]  Karynne E. Patterson,et al.  The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities. , 2015, American journal of human genetics.

[33]  Jay Shendure,et al.  A Multiplex Homology-Directed DNA Repair Assay Reveals the Impact of More Than 1,000 BRCA1 Missense Substitution Variants on Protein Function. , 2018, American journal of human genetics.

[34]  Ivan K. Chinn,et al.  Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles. , 2018, American journal of human genetics.