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

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.

Health and population effects of rare gene knockouts in adult humans with related parents

“…The missing fraction is presumably not seen because they result in early lethality or severe disease incompatible with our selection criteria as healthier adults. This estimate of the fraction of gene knockouts essential for healthy life is lower than previous estimates of ~30% derived from knockout mouse models (5). However it is higher than the 6.4% deficit of below 2% frequency LOF alleles in the Icelandic population obtained from analysis of parent child double transmissions (3), consistent with that analysis having excluded very rare alleles below 0.1% frequency and hence being biased towards mutations that had already been subject to selection.…”

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

“…This may explain, at least in part, the higher yield of our study compared with that by Bloss et al because this has also been shown in a recent review by the Centers of Mendelian Genomics. 21 However, we note here that we cannot exclude the possibility of dual diagnosis and the presence of more than one underlying causal mutation in consanguineous pedigrees as described recently. 22 Second, a distinct dysmorphology profile is present in each of the study families, and this will be much more likely to facilitate "matchmaking" as compared with some of the nonspecific phenotypes reported by Bloss et al (e.g., developmental delay and muscle atrophy).…”

The landscape of human mutually exclusive splicing

“…For one, exome and panel sequencing remains the method of choice for the detection of genetic diseases and both methods rely on current exon annotations (Chong et al , 2015). Furthermore, our data suggest that MXE expression might reflect disease pathogenesis that could allow for the prediction of the affected organ(s).…”