Genetic investigation of patients with tall stature

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-exome 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 two 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 nine 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.