Insights into genetics, human biology and disease gleaned from family based genomic studies

Abstract

Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in novel "disease gene" discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.

Keywords: Centers for Mendelian Genomics (CMG); Mendelian conditions; disease traits; genetic models for disease; rare variant phenotypes.

Figure 1. CMG disease gene discovery through May 30, 2018 (Year 7, Quarter 2) by the four centers.

Discoveries are defined as ‘novel’ if (a) the causal variant was identified in a gene not previously associated with a Mendelian phenotype at the time of case acceptance to the study [i.e. novel gene], or (b) the causal variant was identified in association with a Mendelian phenotype with a MIM number (a known phenotype) and for which no causal variants had previously been reported [i.e. novel gene, unexplained known phenotype], or (c) the causal variant was identified in association with a Mendelian phenotype with no MIM number and for which no variants in the identified gene had been previously reported as causal of a Mendelian phenotype [i.e. novel gene, new phenotype]. Graph of discoveries (genotype-phenotype pairs) categorized as novel, phenotypic expansion, or known. Discoveries are classified as either Tier 1 (blue bars, defined in the text) or Tier 2 (orange bars, not meeting Tier 1 definition). Tier 1 genes include high confidence genes reported by individual centers as Tier 1, defined as having been identified in either (a) multiple kindreds with shared phenotypic features and likely pathogenic variants in the same gene; or (b) a single family plus a model organism with orthologous phenotypic features; or (c) a single family with supportive functional and mapping data. Pheno expan -- phenotypic expansion

Figure 2. Cumulative CMG Disease Gene Discovery.

The number of novel gene-phenotype discoveries as reported by all four centers is graphed by progress reporting period (blue bars) and cumulatively (red bars). Bi-annual phenotypic expansion discoveries involving previously known disease genes (green line) and bi-annual known disease gene discoveries (yellow line) are also graphed. The yellow arrow indicates the pace of novel gene-phenotype discovery, and demonstrates a pace of 263 novel gene-phenotype discoveries per year, or 1 novel gene-phenotype discovery for every 28 ES performed.

Figure 3. Matchmaking tools developed through the CMGs.

(A) The Matchmaker Exchange (MME) facilitates communication among multiple databases of human genomic and phenotypic data, each unique in focus and design. Each database functions as a ‘node’ within the MME. (B) Total number of entries in each MME node, as well as total number of entries per node shared within the MME, are indicated. Also listed is the total number of unique genes per node. Note that a given unique gene may be present in more than one node. (C) Cumulative GeneMatcher statistics demonstrate 26,614 submissions of 10,341 genes through November 1, 2018. This has resulted in 5,195 matched genes. GeneMatcher submitters in 77 countries today, demonstrating world-wide democratization of disease gene discovery. (D) MyGene2 is database through which patients and families can directly share their genomic data. Matchbox is an open-source tool through which institutions or groups with genomic data can connect to the MME.