Hello everyone. I have a technical question I'm currently wrestling with and I could really use some input from clinical geneticists.

As you are aware, most autosomal recessive (AR) disorders are caused by more than one mutation. For relatively common AR disorders, pathogenic mutations have been classified into several categories, based on several criteria. Let's for the sake of this discussion call them 'severe' and 'mild' mutations - for example, F508del and R117H, respectively, in cystic fibrosis. It is usually assumed that homozygosity for a severe mutation (or compound heterozygosity for two severe mutations) is highly penetrant and leads to a severe phenotype in the patient, while homozygosity for a mild mutation (or compound heterozygosity for two mild mutations) is associated with a mild phenotype. Furthermore, in case of mild genotypes, clinical symptoms as well as age of onset tend to be more variable and some individuals may even remain asymptomatic.

My question is the following: can you think of a disorder where compound heterozygosity for a mild and a severe mutation predominantly results in a severe phenotype? For those of you familiar with Ashkenazi Jewish disorders, a comparable case would be the N370S mutation in Gaucher Disease. While homozygosity for N370S is associated with mild, low-penetrant and predominantly adult-onset phenotype, compound heterozygosity with a severe mutation (such as 84insGc or L444P) often leads to a significantly more severe phenotype. [However, this is not a perfect example, as one study in a different (Polish) population found that N370S/N370S resulted in a more severe phenotype than N370S/L444P.]

Any help would be greatly appreciated!