When is it MODY? Challenges in the Interpretation of Sequence Variants in MODY Genes

Abstract

The genomics revolution has raised more questions than it has provided answers. Big data from large population-scale resequencing studies are increasingly deconstructing classic notions of Mendelian disease genetics, which support a simplistic correlation between mutational severity and phenotypic outcome. The boundaries are being blurred as the body of evidence showing monogenic disease-causing alleles in healthy genomes, and in the genomes of individu-als with increased common complex disease risk, continues to grow. In this review, we focus on the newly emerging challenges which pertain to the interpretation of sequence variants in genes implicated in the pathogenesis of maturity-onset diabetes of the young (MODY), a presumed mono-genic form of diabetes characterized by Mendelian inheritance. These challenges highlight the complexities surrounding the assignments of pathogenicity, in particular to rare protein-alerting variants, and bring to the forefront some profound clinical diagnostic implications. As MODY is both genetically and clinically heterogeneous, an accurate molecular diagnosis and cautious extrapolation of sequence data are critical to effective disease management and treatment. The biological and translational value of sequence information can only be attained by adopting a multitude of confirmatory analyses, which interrogate variant implication in disease from every possible angle. Indeed, studies which have effectively detected rare damaging variants in known MODY genes in normoglycemic individuals question the existence of a sin-gle gene mutation scenario: does monogenic diabetes exist when the genetic culprits of MODY have been systematical-ly identified in individuals without MODY?

Figure 1. Relationship between mutational severity in known Mendelian disease-causing genes and clinical phenotype

(A) Traditional, deterministic understanding of Mendelian disease genetics based on biased modes of sample ascertainment. (B) Spectrum-based understanding of Mendelian disease genetics, as revealed by large unbiased population-wide resequencing efforts. This approach encompasses scenarios of incompletely penetrant, monogenic, disease-causing alleles in healthy individuals and, for example, monogenic disorders falsely attributed to a neutral variant in a known risk gene, while the disorder is actually caused by an allele in a different gene.

Figure 2

Recommended guidelines for a systematic and objective approach to identifying, characterizing, and assessing the pathogenicity of rare protein-coding genetic variants.