Diagnostic yield of genetic testing in children with short stature: a systematic review

Objective To synthesize current evidence on genetic testing yield in children with short stature and to identify phenotypic and methodological factors influencing outcomes. The review served as a basis for the development of a consensus guideline on genetic evaluation of short stature. Design Systematic review. Methods Diagnostic yields were calculated by testing modality and clinical characteristics of study cohorts. Results were compared across time periods and recalculated excluding variants of uncertain significance (VUS). Phenotypic features associated with higher yields and the most frequently implicated genes were also analyzed. Results Out of 1163 records, 134 studies were included. The overall diagnostic yield was 4.7% for candidate gene testing (n = 78), 16.3% for chromosomal microarray (n = 8), 21.6% for gene panels (n = 14), and 33.3% for exome sequencing (ES) (n = 39). After exclusion of VUS, the reestimated yields were lower for all approaches. ES approaches yielded higher diagnostic rates in syndromic short stature (50.8%, n = 15) compared to isolated short stature (15.1%, n = 13). Among 45 studies evaluating predictive factors, facial dysmorphism (68.2%) and skeletal abnormalities (61.1%) were most strongly associated with increased diagnostic yield. Recurrently identified genes included PTPN11, NF1, COL2A1, ACAN, and FGFR3. Conclusions Genetic testing substantially improves the diagnostic process in children with isolated and syndromic short stature. Diagnostic yield varies by testing modality and phenotype, with higher rates observed using comprehensive genomic methods and in individuals with dysmorphic or syndromic features. Frequently implicated genes highlight common biological pathways involved in growth regulation, underscoring the utility of genetic evaluation in this population.