Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature |
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| Institution: | 1. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany;;2. Institute of Medical and Molecular Genetics (INGEMM) and Skeletal Dysplasia Multidisciplinary Unit (UMDE), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, and CIBERER, Madrid, Spain;;3. Department of Orthopaedic Rheumatology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany;;4. Institute of Human Genetics, Otto-von-Guericke University Magdeburg, Magdeburg, Germany;;5. Institute of Human Genetics, University of Leipzig, Leipzig, Germany;;6. Institute of Human Genetics, University of Wuerzburg, Wuerzburg, Germany;;7. Institute of Human Genetics, University of Essen, Essen, Germany;;8. Institute of Human Genetics, University of Düsseldorf, Düsseldorf, Germany;;9. Institute of Medical Genetics, University of Zurich, Zurich, Switzerland;;10. Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany;;11. Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. |
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| 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. |
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