A certain proportion of patients with Mendelian diseases are overlooked, although substantial technical advances in molecular genetics have been achieved. Massively parallel sequencing (MPS) increasingly identifies genetic variants of unknown significance, which may remain clinically unhelpful. Furthermore, difficult niches in the genome exist, which cannot be solved by standard MPS. In the reported family autosomal dominant kidney disease leading to renal failure in middle adulthood runs through the maternal and paternal family.