Exome sequencing of patients with syndromic tall stature reveals four novel candidate genes

This study aimed to evaluate a cohort of patients with syndromic tall stature of unknown etiology via exome sequencing (ES) to identify novel candidate genes for overgrowth conditions. We enrolled 37 patients with heights greater than the 97.7th percentile and syndromic features. The ES analysis first focused on rare deleterious single nucleotide and copy number variants in genes previously associated with overgrowth conditions. For patients in whom diagnosis of a known tall stature disorder could not be achieved, we performed analysis for candidate genes. The search considered deleterious variants in constrained genes that were linked with height in association studies, animal models consistent with the proposed phenotype, and/or variants recurrent in the literature or our cohort. Genetic diagnosis was established in 11 patients. Pathogenic or likely pathogenic variants were identified in FBN1, PTEN, NSD1, SUZ12, CDH8, and DEPDC5. One patient carried a likely pathogenic mutation in FBN2 and a pathogenic mutation in COL5A1. Furthermore, in two patients, we identified large pathogenic deletions confirmed by chromosomal microarray analysis. Candidate gene analysis uncovered four genes potentially associated with tall stature in five patients: PTCH1, SST, KDM4A, and GRB10. PTCH1 and SST were identified in patients with whole gene deletions. Two unrelated patients were found to have the same rare missense variant in KDM4A. In conclusion, exome sequencing analysis had a diagnostic yield of 29.7% in a cohort of patients with syndromic tall stature and we identified four novel candidate genes that are involved in overgrowth conditions.