Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature

Abstract

PurposeShort stature is a common condition of great concern to patients and their families. Mostly genetic in origin, the underlying cause often remains elusive due to clinical and genetic heterogeneity.MethodsWe systematically phenotyped 565 patients where common nongenetic causes of short stature were excluded, selected 200 representative patients for whole-exome sequencing, and analyzed the identified variants for pathogenicity and the affected genes regarding their functional relevance for growth.ResultsBy standard targeted diagnostic and phenotype assessment, we identified a known disease cause in only 13.6% of the 565 patients. Whole-exome sequencing in 200 patients identified additional mutations in known short-stature genes in 16.5% of these patients who manifested only part of the symptomatology. In 15.5% of the 200 patients our findings were of significant clinical relevance. Heterozygous carriers of recessive skeletal dysplasia alleles represented 3.5% of the cases.ConclusionA combined approach of systematic phenotyping, targeted genetic testing, and whole-exome sequencing allows the identification of the underlying cause of short stature in at least 33% of cases, enabling physicians to improve diagnosis, treatment, and genetic counseling. Exome sequencing significantly increases the diagnostic yield and consequently care in patients with short stature.

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).