Diagnostic Yield of Genetic Testing in Children with Short Stature: a Systematic Review

Renata C. Scalco, Genetic Endocrinology Unit (LIM25), Endocrinology Division, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil.
Jan W. Schoones, Directorate of Research & Valorisation, Leiden University Medical Center, Leiden, the Netherlands.
Despoina Galetaki, Division of Endocrinology, Children's National Hospital, Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Ana M. Santillan-Vasconez, Genetic Endocrinology Unit (LIM25), Endocrinology Division, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil.
Gabriela J. Kim, Genetic Endocrinology Unit (LIM25), Endocrinology Division, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil.
Laurana P. Cellin, Genetic Endocrinology Unit (LIM25), Endocrinology Division, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil.
Melanie Babinski, Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, MA.
Raissa C. Rezende, Genetic Endocrinology Unit (LIM25), Endocrinology Division, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil.
Ola Nilsson, Division of Pediatric Endocrinology (ERN BOND, ENDO ERN) and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
Stefano Cianfarani, Department of Systems Medicine, University of Rome 'Tor Vergata'.
Jan M. Wit, Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands.
Andrew Dauber, Division of Endocrinology, Children's National Hospital, Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Olaf M. Dekkers, Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
Alexander A. Jorge, Genetic Endocrinology Unit (LIM25), Endocrinology Division, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil.

Document Type

Journal Article

Publication Date

1-16-2026

Journal

European journal of endocrinology

DOI

10.1093/ejendo/lvag011

Keywords

diagnostic yield; genetic testing; short stature; systematic review

Abstract

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 1,163 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 re-estimated 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 dysmorphisms (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.

Department

Pediatrics

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