Complexity of Genotype-Phenotype Correlations in Mendelian Disorders: Lessons from Gaucher Disease

TLDR: A careful evaluation of one specific Mendelian disorder, Gaucher disease, can learn lessons directly applicable to other diseases, both rare and common, that will help to better understand the complexity in interpreting genetic data in multigene disorders.

Abstract: Mendelian disorders are diseases which occur due to a mutation in the DNA sequence of a single gene. However, as we learn more about these inherited diseases, it is clear that there can be a vast spectrum of associated phenotypes. Gaucher disease is an example of a “simple” monogenic disorder with complex features. It results from the deficiency of the recessively inherited enzyme glucocerebrosidase, and is the most common lysosomal storage disorder. One of the chief clinical challenges facing geneticists and medical practitioners is to assess how adequately one can use genotype data to predict phenotypes. The ability to make such predictions is an essential tenet of individualized medicine and has implications for prenatal decision making. By understanding the limitations of genotype-phenotype correlation in monogenic disorders, we can gain insights that will help us to better understand the complexity in interpreting genetic data in multigene disorders. Factors including genetic modifiers, gene-gene interaction, reduced penetrance, imprinting, processed and non-processed pseudogenes, regulatory polymorphisms, epigenetics and the abundant number of private mutations, provide challenges for those seeking to understand genetic contributions to distinct phenotypes. Through a careful evaluation of one specific Mendelian disorder, Gaucher disease, we can learn lessons directly applicable to other diseases, both rare and common.