Establishing the relevance of a genetic variant in the causality of a given disease is crucial. Clinical molecular geneticists use a variety of tools including mode of inheritance, segregation in the family, penetrance, and determination of the variant as loss of function (LOF) or gain of function (GOF). However, this approach to determining how a variant causes disease comes into question when variants appear to cause both LOF and GOF at different times in a patient’s lifetime (hyperinsulinism [HI] at birth due to LOF and diabetes either at birth or in later years due to GOF). This, in turn, impacts the mechanism(s) of disease and ultimately the diverse phenotypes that LOF or GOF in the same gene can determine. In genes that control insulin secretion, there is the added complexity that HI leads to premature apoptosis of β-cells potentially causing premature β-cell failure and diabetes, thus mimicking a change from LOF to GOF ( 1 ). In their article in this issue of Diabetes, Scala et al. ( 2 ) describe a series of patients presenting with a phenotype consistent with maturity-onset diabetes of the young (MODY) and the surprising finding of LOF in ABCC8 variants and propose that there are two distinct forms of K ATP channel–associated MODY. Their article, and the questions they raise, indicates that for the general endocrinologist/diabetologist interpretation of genetic tests requires a far more complex understanding than simple Mendelian inheritance. This complexity, specifically in ABCC8, suggests the need for consulting with geneticists and experts in the specific disease and genes and that, for laboratories reporting genetic testing, much more careful and specific interpretation needs to be provided to the ordering physician.
