Figure 1

Flowchart gene discovery approach. We built a study group of 565 individuals with short stature or growth retardation (Table 1). Systematic phenotyping and targeted diagnostic testing of common and recognizable causes in all 565 patients led to a diagnostic yield of 13.6% (Supplementary Table 1). Detailed information about the systematic phenotyping is provided in the Methods section in the Supplementary Data. For 200 representative individuals where no underlying cause could be determined (Table 1), we performed whole-exome sequencing, which increased the diagnostic yield by 17% up to 33% by the identification of mutations in known short stature–associated genes (Table 2, Supplementary Tables 3–4). Genotype–phenotype re-evaluation confirmed that these patients present with only part of the characteristic symptomatology. The additional diagnostic yield already had direct effects in preventive measures, symptomatic and targeted treatment in 15.5% of the 200 exome-sequenced patients (Table 4 and Supplementary Table S6).