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Review
. 2015 Aug 6;97(2):199-215.
doi: 10.1016/j.ajhg.2015.06.009. Epub 2015 Jul 9.

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

Jessica X Chong  1 , Kati J Buckingham  1 , Shalini N Jhangiani  2 , Corinne Boehm  3 , Nara Sobreira  3 , Joshua D Smith  4 , Tanya M Harrell  1 , Margaret J McMillin  1 , Wojciech Wiszniewski  5 , Tomasz Gambin  5 , Zeynep H Coban Akdemir  5 , Kimberly Doheny  6 , Alan F Scott  7 , Dimitri Avramopoulos  7 , Aravinda Chakravarti  7 , Julie Hoover-Fong  3 , Debra Mathews  8 , P Dane Witmer  6 , Hua Ling  6 , Kurt Hetrick  6 , Lee Watkins  6 , Karynne E Patterson  4 , Frederic Reinier  4 , Elizabeth Blue  9 , Donna Muzny  2 , Martin Kircher  4 , Kaya Bilguvar  10 , Francesc López-Giráldez  10 , V Reid Sutton  5 , Holly K Tabor  11 , Suzanne M Leal  12 , Murat Gunel  10 , Shrikant Mane  10 , Richard A Gibbs  13 , Eric Boerwinkle  14 , Ada Hamosh  3 , Jay Shendure  4 , James R Lupski  15 , Richard P Lifton  16 , David Valle  3 , Deborah A Nickerson  4 ; Centers for Mendelian Genomics; Michael J Bamshad  17
Affiliations
Review

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

Jessica X Chong et al. Am J Hum Genet. .

Abstract

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.

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Figures

Figure 1
Figure 1
Clinical Diagnostic Rates of Mendelian Conditions for which Gene(s) Have Been Identified All Mendelian conditions, or phenotypic series, included are listed in GeneReviews and might be genetically heterogeneous (i.e., caused by mutations in one or more genes). (A) Histogram of the percentage of individuals who had a Mendelian condition (x axis) and who received a corresponding molecular diagnosis from clinical testing. Collectively, for 292 Mendelian conditions, a causal variant could be identified in only ∼52% of affected subjects overall. (B) Boxplots show the molecular diagnostic rate (y axis) for Mendelian conditions organized by the number of causal genes (x axis). The diagnostic rate per condition is inversely correlated with the level of genetic heterogeneity (Spearman correlation ρ = −0.155, p value = 0.008019).
Figure 2
Figure 2
Relationship between Human Protein-Coding Genes and Mendelian Phenotypes Of approximately ∼19,000 protein-coding genes predicted to exist in the human genome, variants that cause Mendelian phenotypes have been identified in ∼2,937 (∼15.5%; orange squares). Genes underlying ∼643 Mendelian phenotypes (∼3.38%; gray squares) have been mapped but not yet identified. On the basis of analysis of knockout mouse models, LOF variants in up to ∼30% of genes (∼5,960; red squares) could result in embryonic lethality in humans. Note that the consequences of missense variants in these genes could be different. For a minimum of ∼52% of genes (∼10,330; blue squares), the impact in humans has not yet been determined. Collectively, ∼16,063 genes remain candidates for Mendelian phenotypes.
Figure 3
Figure 3
Relationship between GWAS Signals and Genes Underlying Mendelian Phenotypes (A) Plot of the fraction of GWAS-signal genes that are also implicated in Mendelian phenotypes (MPs). Each orange dot represents the proportion of GWAS signals that, in a sliding window of 500 GWAS signals, are mapped to a gene also known to underlie a Mendelian condition. In GWAS signals, approximately 26.6% of genes with the top 500 lowest p values underlie a Mendelian phenotype. In contrast, only 14.2% of genes overall are known to underlie a Mendelian phenotype, suggesting that GWAS signals are more likely to be enriched with genes implicated in Mendelian phenotypes. Varied colored dots represent the percentage of genes underlying a Mendelian phenotype in GWAS signals underlying different phenotypic categories as follows (of increasing percentages from bottom to top): 10% for reproductive traits (blue); 11% for respiratory traits (gold); 13% for autoimmune inflammatory traits (dark green); 16% for immunologic traits (blue); 17% for mental-health traits (teal); 19% for infectious-disease traits (gray); 21% for anthropometric traits (brown); 23% for cancer (red); 25% for cardiovascular traits (tan); 26% for metabolomics traits (yellow); 28% for pharmacogenetic traits (green); and 33% for musculoskeletal traits (blue). (B) Cumulative plot of the proportion of GWAS signals in which a gene underlying a Mendelian phenotype (MP) was found (orange dots) and GWAS signals in which a gene underlying a Mendelian phenotype was not found (gray dots). At virtually every p value, a higher proportion of GWAS signals overlapped genes underlying Mendelian phenotypes.
Figure 4
Figure 4
Approximate Number of Gene Discoveries Made by WES and WGS versus Conventional Approaches since 2010 Since the introduction of WES and WGS in 2010, the pace of discovery of genes implicated in Mendelian phenotypes per year has increased substantially, and the proportion of discoveries made by WES or WGS (blue) versus conventional approaches (red) has steadily increased (see Supplemental Material and Methods for a detailed description of the analysis). Since 2013, WES and WGS have discovered nearly three times as many genes as conventional approaches.
Figure 5
Figure 5
Overview of Deliverables from the CMGs Collectively, the CMGs have worked with 529 investigators from 36 countries to collect and sequence 16,226 exomes and 96 genomes. Analyses of these data have resulted in 956 discoveries. These discoveries, as well as tools and technical methods developed by the CMGs, have led to the publication of 146 manuscripts.
Figure 6
Figure 6
Worldwide Interactions with the CMGs In collaboration with 529 investigators representing 261 institutions in 36 countries (or 1 of every 5 countries [orange] in the world), the CMGs have collected 18,863 samples from 8,838 families. Approximately 60% (n = 20) of these countries are located outside of North America, Europe, or Australia.
Figure 7
Figure 7
Criteria for Establishing Causality of Discoveries Flow diagram of decisions and criteria used for establishing whether gene discoveries by CMGs (Table 2) were considered causal by conservative or suggestive guidelines.
Figure 8
Figure 8
Breakdown of Discoveries Made in the 1,049 Mendelian Phenotypes Assessed in the CMG Pipeline Phenotypes entering the CMG pipelines are putatively either new phenotypes or unexplained, known phenotypes. A substantial fraction (i.e., 32%) of phenotypes were found to have causal variants in known genes, consistent with explained, known phenotypes. However, a larger fraction (40%) of phenotypes assessed resulted in discoveries of novel genes in addition to the expansion of 198 Mendelian phenotypes. For ∼28% of phenotypes assessed, no causal variant has yet been discovered. Novel genes are those that were not associated with any Mendelian phenotype when a project was accepted by the CMGs. Phenotypes are defined on a gene- and/or genotype-centric basis—if a novel gene was discovered for a known, explained phenotype, the phenotype was reclassified as a novel phenotype because it is almost certain that deeper phenotyping would reveal (molecular, biochemical, or physiological) differences that distinguish the novel phenotype from the previously known, explained phenotype caused by mutations in another gene.
Figure 9
Figure 9
Discovery Metrics under Different Models of Inheritance for Mendelian Phenotypes Studied by the CMGs (A) The percentage of Mendelian phenotypes for which a gene was discovered on the basis of conservative causality criteria per different models of inheritance with mapping data (dark green) or without mapping data (light green) is shown. Also shown is the percentage of Mendelian phenotypes for which a causal gene was not found per different models of inheritance with mapping data (dark gray) or without mapping data (light gray). Note that for most phenotypes analyzed under an autosomal-recessive homozygous model that failed, mapping data were available; however, the statistical significance of the mapping data varied (e.g., number and length of runs of homozygosity, magnitude of LOD score, etc.). The mean number of genes discovered per Mendelian phenotype was 0.52 or 0.76 on the basis of only conservative or combined conservative and suggestive criteria, respectively. These figures do not include results from persons found to have more than one Mendelian phenotype. (B) Classification of discoveries of genes underlying Mendelian phenotypes as known (white squares) or novel (blue squares). (C) Percentage of Mendelian phenotypes for which a novel discovery (dark blue) or known discovery (light blue) was made on the basis of conservative causality criteria per different models of inheritance. The mean number of novel discoveries per Mendelian phenotype was 0.52 or 0.66 on the basis of only conservative or combined conservative and suggestive criteria, respectively. Abbreviations are as follows: AD, autosomal dominant; AR, autosomal recessive (when recessive inheritance was clear, but analysis of both consanguineous and non-consanguineous families contributed to the discovery); AR homozygous, autosomal recessive in a consanguineous family; AR heterozygous, autosomal recessive in a non-consanguineous family (i.e., compound-heterozygous mutations).
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