The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.

By Jessica X. Chong, K. Buckingham, S. Jhangiani, Corinne Boehm, N. Sobreira, J. Smith, Tanya M. Harrell, M. McMillin, W. Wiszniewski, T. Gambin and 32 more. 2015

611 citations recorded by the source corpus.

Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.

Subfields: Genetics

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

Citations in the corpus

Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes (2020, methodology): “Instead of being computationally ﬁ ltered by read quality, the 129 putative MNVs (16 gained nonsense mutations, 110 changed missense with high CADD score and low gnomAD MNV frequency, and 3 gained missense) went through manual inspection by the analysts at the Center for Mendelian Genomics (CMG) at ”
Mendelian Gene Discovery: Fast and Furious with No End in Sight. (2019, background): “, a gene not previously known to underlie an MC [novel gene] or a gene found to underlie a novel condition or known but unexplained MC); (2) enabled identification of >1,000 new MCs; (3) replaced ‘‘phenotype-driven’’ with ‘‘genotype-driven’’ syndrome delineation; (4) led to the deconstruction of heu”
Integrative omics for health and disease (2018, background): “However, the adoption of clinical genomics has expanded rapidly over the past few years from the first successful diagnosis 1 to multi-institutional and international adoption 72 .”
Insights into genetics, human biology and disease gleaned from family based genomic studies (2019, positive): “An analysis of genes associated with rare disease revealed that almost 20% were nearest to, or contain, a variant that had been associated with common disease.(21) Moreover, rare de novo SNVs with large phenotypic effect contribute to common childhood traits including neurodevelopmental and congenit”
Mutation severity spectrum of rare alleles in the human genome is predictive of disease type (2019, background): “Genetic variations are major determinants of human diseases and phenotypes [1].”
Genomic diagnosis for children with intellectual disability and/or developmental delay (2016, background): “Given the rates of progress in Mendelian disease genetics [36] and the development of new genomic annotations, we believe that systematic reanalysis of genomic data should become standard practice.”