Genetic investigation of patients with tall stature
European Journal of Endocrinology
Context: Patients with tall stature often remain undiagnosed after clinical investigation and few studies have genetically assessed this group, most of them without a systematic approach. Objective: To assess prospectively a group of individuals with tall stature, with and without syndromic features, and to establish a molecular diagnosis for their growth disorder. Design: Screening by karyotype (n=42), chromosome microarray analyses (CMA) (n=16), MS-MLPA (n=2) targeted panel (n=12) and whole
... ome sequencing (n=31). Patients and methods: We selected 42 patients with tall stature after exclusion of pathologies in GH/IGF1 axis and divided them into syndromic (n=30) and non-syndromic (n=12) subgroups. Main outcome measures: Frequencies of pathogenic findings. Results: We identified 2 patients with chromosomal abnormalities including SHOX trisomy by karyotype, one 9q22.3 microdeletion syndrome by CMA, two cases of Beckwith-Wiedemann syndrome by targeted MS-MLPA analysis and 9 cases with heterozygous pathogenic or likely pathogenic genetic variants by multigene analysis techniques (FBN1=3, NSD1=2, NFIX=1, SUZ12=1, CHD8=1, MC4R=1). Three of 20 patients analyzed by WES had their diagnosis established. Only one non-syndromic patient had a definitive diagnosis. The sequential genetic assessment diagnosed 14 out of 42 (33.3%) tall patients. Conclusion: A systematic molecular approach of patients with tall stature was able to identify the etiology in 13 out of 30 (43.3%) syndromic and 1 out of 12 (8.3%) non-syndromic patients, contributing to the genetic counseling and avoiding unfavorable outcomes in the syndromic subgroup.