Suzanne de Bruijn

301 General discussion and perspectives 3. Looking beyond Mendelian genetics Inherited HL and RD are generally considered monogenic disorders that follow the laws of Mendel. However, the increasing reports of high inter- and intrafamilial phenotypic variability that can be associated with a single pathogenic variant, and the occurrence of incomplete penetrance, show that this picture is far from complete. In view of missing heritability, shifting our attention from monogenic (Mendelian) inheritance towards oligogenic, polygenic or multifactorial inheritance could be a crucial next step. Instead of a black-white division between monogenic and multifactorial diseases, one should consider a continuum from monogenic diseases, via near-Mendelian traits to complexmultifactorial diseases with a large environmental component ( Figure 3 ). There is an inverse relationship between variant allele frequencies and variant effect sizes. For some disorders, such as age-related HL and macular degeneration, multifactorial inheritance is clear. For other disorders assumed to be monogenic for decades, such as DFNA21 and a subset of Stargardt disease cases, a near-Mendelian inheritance is likely to be a better fit. The heritability of age-related HL is estimated to be 35% to 70%. 117 GWAS studies have indicated that age-related HL is highly polygenic in nature, although several genetic risk loci could be identified. 56,57 These data confirm that the genetic risk to develop age-related HL is determined by a combination of common variants (population allele frequency >5%) with small effect sizes. Stargardt disease, on the other hand, has been considered a monogenic disorder for years, where biallelic pathogenic variants in ABCA4 cause macular disease. Today, Stargardt disease cases carrying the mild p.(Asn1868Ile) variant in trans with a severe ABCA4 variant, are considered being non-Mendelian. This is based on the high population allele frequency of this mild variant (~6%), the identification of unaffected individuals carrying the p.Asn1868Ile variant in trans with a severe ABCA4 variant, and an imbalance in sex ratio in patients with this genotype. 118 As proposed by Runhart et al., approximately 25% of the Stargardt disease cases show oligogenic, polygenic or multifactorial inheritance, and together with other (unidentified) modifiers, sex should be considered as a potential disease-modifying variable. 118,119 Similarly as for Stargardt disease, it can be argued that DFNA21 also is a near-Mendelian disorder. Recently, we learned that the c.1696_1707del RIPOR2 variant that underlies DFNA21 is presumed to be the most frequent cause of inherited adult-onset HL in Northwest Europe. In the Netherlands, 13,000 individuals are estimated to carry this variant and they are therefore at risk to develop HL. One of the most essential remaining questions is whether all carriers will develop HL during life, or that other (non-)genetic protective or damaging modifiers are involved as well. Based on the DFNA21-affected