Fig. 1

The clinical pathway as a flowchart. Following conventions for flowcharts, rounded rectangles indicate start or end of a process, rectangles represent actions, and rhombuses binary decisions. Vertical arrows starting from rhombuses always point to the next step if the answer is yes, horizontal arrows point to the next step if the answer is no. Circled numbers 1 to 23 refer to the explanation of the particular step in the text. 3 + i with i = 0, 2, 3, ….: in step 7 for i = 0 the third case conference coordinates treatment and care for the first time. When results of the evaluation of treatment and care in step 9 are fed back to step 7, the conference deciding continuation or modification of treatment and care is the 3 + 2 = 5^th case conference, and so on. 4 + j with j = 0, 2, 3, 4, …: in step 15 for j = 0 it is the 4^th case conference. If in step 16 PDx is not confirmed, and in Step 22 (the 5^th conference) it is decided to perform further innovative diagnostics, than returning to step 14, the number of the case conference will be 4 + i = 2, i.e. the 6^th conference, and so on. Presumptive (P) Dx|Biomarker, clinical Phenotype: presumptive diagnoses given Biomarker or clinical Phenotype; the symbol (|) is to be read as “in case of”. Dx: Diagnosis, F⁺: false positive, NBS: newborn screening, PDx: presumptive diagnosis, T⁺: true positive, WES: whole exome sequencing