Suzanne de Bruijn

302 Chapter 6 families described in chapter 3.1 , the RIPOR2 related phenotype can be considered highly variable with an age of onset that ranges from congenital to 70 years. Also within families, significant phenotypic variability in age of onset and severity of HL can be observed. These data suggest that genetic and/or environmental modifiers are likely to contribute to the phenotypic outcome. In chapter 3.1 , some effort was taken to identify potential modifiers such as noise exposure or RIPOR2 transcript levels in blood, but no potential modifier was found yet. More in-depth studies, that are focused on including a larger patient cohort and investigating more relevant tissue samples, should be performed. Additionally, in view of genotype-phenotype correlations and the understanding the potential near-Mendelian inheritance of DFNA21, a large natural history study should be initiated to gain a full understanding of all aspects of RIPOR2 - associated HL. Besides the possibilities of digenic, oligogenic, polygenic, and multifactorial inheritance patterns, also other non-Mendelian inheritance patterns should receive more attention in diagnostic pipelines. Variant effect size Allele frequency Monogenic Near-Mendelian Multifactorial Oligogenic Polygenic Figure 3. Continuum of monogenic to polygenic disorders. The spectrum of inherited disorders can be considered a continuum, with monogenic disorders as one of the extremes and associated with rare variants with a large effect size, via near-Mendelian disorders, towards oligogenic, polygenic or multifactorial disorders that are caused by a combination of common variants with small effects sizes and an increased contribution of environmental factors.